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Pharmacology Cito

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Dear future physicians and pharmaceutists! The scientific and pedagogical staff of the department of the National University of Pharmacy (Kharkiv) presents a new textbook "Pharmacology – Cito!" to you. We want to change the myth that it is impossible to learn pharmacology quickly and qualitatively. The textbook "Pharmacology – Cito!" is published for those, who have decided to connect his or her profession with medicines, but think that a great amount of the information in pharmacology is hard to learn. Taking this fact into account we have decided to help those, who wish to master pharmacology in logical, fast - "Cito!"- version.

Not be afraid of pharmacology! The 40-year experience of teaching pharmacology testifies that for the last 10-15 years a tendency of reducing the amount of classroom hours in pharmacology because of increasing the amount of the individual work is being observed. However, because of the lack of time and the constant increasing volume of information in pharmacology, everyone has not enough time to master it soundly and qualitatively. This textbook trains future pharmaceutists and physicians in the pharmacological logic, i.e. knowing the mechanisms of action one can understand their , naturally, on the basis of pharmacodynamics one can find logically the indications to their application and from their side effects the contraindications can be seen. The information about the peculiarities of medicines has been generalized and given as a pharmacological ―face‖ in tables. The volume of this textbook in pharmacology is sufficient for acquiring the confidence in the opportunity of the further improving of knowledge in this discipline, which is important for a physician and a pharmaceutist. Here we have concentrated such amount of information that is necessary enough for getting a pharmacological "portrait" of new and traditional medicines; we have provided physicians, pharmaceutists and students with the algorithm of the pharmacological logic, thinking and intuition. Today the assortment of medicines, which a physician and a pharmaceutist are ―armed‖ with, is more than 400 thousand trademarks. The textbook gives the information on those blockbusters, brands and generics of the world pharmacy, without knowing them either a physician or a pharmaceutist cannot ―step over the threshold‖ of a ward and a chemist’s shop; every physician and pharmaceutist should know them. Frequently the insufficient survivability of knowledge in the basic subjects (pathology, physiology, biochemistry) has obliged us to help those, who had lost this knowledge. That’s why in the section "Glossary" we have reminded you the terms and concepts, which you had known, but forgot. The unique feature of this textbook is the presentation of the information, which corresponds to the credit-module organization of the academic process according to the European educational standards. This textbook is the first step for those, who want to succeed in pharmacotherapy, to master the pharmacological logic. Despite of the conciseness description of a "pharmacological face" of each pharmacological group all the elements of the drug characteristics in the textbook (INN and trade names, the mechanism of action, pharmacodynamics, indications, side effects and contraindications) are presented at the advanced up-to-date level. The authors hope that "Pharmacology – Cito!" (the pharmacological logic) will be the start for further improving your pharmacological knowledge. This edition is intended for students, physicians and pharmaceutists, who want to catch everything in this life!

With sincere hope for mutual understanding, professor S. Drogovoz

Special thanks to Pozdnyakova A.Yu., Sadovnikova M.V., Labuzova Yu.V.

6 GENERAL PHARMACOLOGY (“PHARMACOLOGICAL ALPHABET”)

PHARMACOLOGY AND ITS BASIC TERMS

Pharmacology in its literal translation means ―the science about medicines‖ (Pharmakon in Greek is ―medicine, poison‖; logos in Latin means ―science‖). Nowadays pharmacology is a complex science studying the action of medicines on healthy and diseased organisms, the science about the purposeful search of new medicines and their rational use. A future physician and a pharmaceutist must understand clearly the actual meaning of common terms (approved by the WHO), which characterize and changes in the organism occurred after their introduction. A medicine (drug, , remedy, medicinal agent) is a pharmacological agent in a definite medicinal form approved for application with the purpose of treatment, prophylaxis and diagnostics of diseases. A medicinal substance is an individual pharmacological substance approved for application. A pharmacological substance is an individual substance with the pharmacological activity under research. A pharmacological agent (remedy) is a pharmacological substance or their combination in a definite medicinal form under research. Other names of medicines are pharmaceutical agent, physiologically, biochemically and pharmacologically active substance. These names are lame or unpractical synonyms for the word ―medicine‖. A medicinal form is the form of a medicine, which is convenient for use, appropriate for the aims of therapy and provides the required effect. Medicines introduced into the organism interact with the cell receptors, as a result functions of cells intensify (stimulate) or suppress (inhibit). The intensification or suppression of biophysical, biochemical and physiological processes in a cell under the action of medicines is called a pharmacological reaction. A pharmacological effect is the result of the successive changes in the functions of the organism’s organs and systems under the action of medicines. The complex of changes (pharmacological effects), which takes place in the organism under the influence of medicines, is called pharmacodynamics or pharmacological properties of a medicine. The method, by which a medicine’s pharmacological effect is achieved, is called the mechanism of its action.

THE MECHANISM OF DRUGS’ ACTION

To reveal its pharmacological effect that is realized via the mechanism of action, a medicine must contact with of the organism’s cells. A contact of a medicine with a biological substrate – (ligo means ―to connect‖) can occur with the help of chemical, physical, physicochemical interaction. Receptors, , ion channels, transport systems and others are the primary ―targets‖ for medicines. Receptors are specific cell structures, which provide the interaction between a medicine and the organism. They interact only with medicines that have a certain chemical structure, i.e. they possess the property of selectivity.

7 The typical mechanisms of drug and interaction: 1. A medicine that has structural similarity to a metabolite (for example, mediator) interacting with the receptor promotes its excitation (imitating the mediator’s action). Such medicine is called (in Greek agonistes is ―a rival‖, agon is ―a struggle‖) or mimetic (in English ―to mimic‖). Durability of a medicine binding to certain receptors is stipulated by their structure and it is termed as “affinity” (in Latin affinis is ―relative‖). 2. A medicine is similar to a metabolite; it binds to a receptor, but does not give a chance to a true metabolite to bind to a receptor causing effects opposite to the metabolite. Such medicines are called antagonists or blockers (antagonista is ―rivalry‖). 3. Acting on the receptors medicines can combine the properties of and antagonists. In this case they are called agonists-antagonists. 4. When interacting with the receptor’s allosteric centre medicines promotes the conformational changes in the structure of the receptor modifying its sensitivity to the organism’s metabolites. They are medicines - modulators. Many medicines modify the functioning of the ion channels. One of the ―targets‖ for medicines are potential-depending ion channels that conduct Na+, K+, Ca2+ selectively through the cell membrane. Medicines can block potential-depending ion channels (break the penetration of ions by channels through the cell membrane) or activate these channels (assist their opening and passing of ion flows). The variants of the drug action mechanisms listed above do not exhaust all possibilities of their interaction with the body cells. Nowadays the mechanism of action has not been found for all medicines.

TYPES OF THE DRUG ACTION

To analyze complex and various phenomena of pharmacodynamics there are several types of the drug action. Local (preresorptive) action is all changes occurring in the site of the drug application. The local action is revealed if a medicine is applied on the skin, mucous membranes and is directly introduced into organs. It should be remembered that the local action cannot be considered separately from the reaction of the whole organism. The local action is characterized, for example, by astringent, irritant, cauterant, local effect of medicines. To reveal the local action ointments, gels, solutions for external use, powders, pastes, and plasters are often used. The resorptive action (in Latin resorbeo means ―I absorb‖) appears when a medicine absorbs in the and can develop effects in the different organs and tissues that it interacts with. There is a direct and indirect resorptive action. The direct action is the effect caused by a direct influence of a medicine on the target organ. The indirect effect appears indirectly in other organs and tissues and it is a result of the drug’s direct action. For example, the improvement of the cardiac activity under the influence of cardiac glycosides (direct action) leads to the normalization of the blood circulation and increase of diuresis (indirect action). The direct action is always primary, the indirect one is secondary. The subtype of the drug’s direct action is the selective action, i.e. the influence of the medicine only on the limited group of cells, organs.

8 Reflex action is the indirect action of a medicine, in which mechanism of reflexes development take part. The reflex action is carried out distantly and it is the consequence of the afferent nerves endings stimulation. For example, the ammonium hydroxide while inhaling irritates the mucous membrane receptors of the respiratory tract and stimulates the respiratory and vasomotor centres by reflex. The main action and side effect of medicines are distinguished. The main (positive) action is a desirable action, it is for it the medicine is used. The side effect (negative) action, as a rule, is undesirable action of the medicine and it can impede the main action. There are also reversible and irreversible actions. If the changes in the organism occurring as a result of the drug’s action disappear without any consequences over a period of time, then a medicine possesses a reversible action. In opposite case the irreversible action takes place. The drug action also subdivides into pharmacotherapeutic and negative. The one determines, where a medicine acts treating a disease (the cause, pathogenesis, symptoms); the other is used for characterizing the safety of the drug’s use. Nowadays pharmacotherapy uses medicines with etiotropic, pathogenetic, symptomatic, stimulative and substitutive actions. The etiotropic (causal) pharmacotherapy is directed to elimination of the disease’s cause. As etiotropic therapy chemotherapeutic, antihelminthic, -containing medicines and some are used. Medicines with the pathogenetic type of action are those, which eliminate or decrease functional and structural abnormalities arised in the process of the disease’s development (pathogenesis). As pathogenetic therapy anti- inflammatory, antihistaminic medicines and cardiac glycosides are used. The ―oldest‖ type of pharmacotherapy is symptomatic, which is directed to elimination of the disease’s symptoms. This type of treatment is palliative (in Latin pallio is ―to mask, to smooth‖). In this case medicines with the symptomatic action such as , spasmolytics, antihypertensives, antipyretics, etc. are applied. The stimulation pharmacotherapy is directed to increase of host defences (the process of sanogenesis) and stimulate the organism’s compensatory mechanisms. This is the least developed type of the drug therapy. , actoprotectors, adaptogens, some possess a stimulating action. In a number of cases the substitution (replacement) pharmacotherapy is used. It is directed to restore deficiency of substances not produced in the sufficient amount in the organism (vitaminous, enzymatic, hormonal therapy).

THE NEGATIVE EFFECTS OF DRUGS

Cumulation (in Latin cumulatio means ―accumulation‖) develops due to the accumulation of a medicine in the organism (material cumulation) or summation of its effects when after of the medicine the changes caused by it remain for a long time (functional cumulation). The material cumulation is typical for cardiac glycosides, salts of heavy metals, ; the functional one is for ethyl . Sometimes the cumulation phenomenon is used to achieve the required therapeutic effect of the medicine (for example, cardiac glycosides). Habituation (syn. steadiness, tolerance; tolerantia means ―endurance, resistance‖) is the state when the effectiveness of medicines decreases with their repeated administration. A

9 rapid drug habituation is called tachyphylaxis (tachys means ―rapid‖, phylaxis is ―protection‖). It is typical for naphthizin, ephedrine hydrochloride. Addiction (drug dependence) is characterized by an overmastering desire to use a medicine regularly. As a rule, addiction appears to the drugs that cause (e.g. analgesics). Abstinence is a feeling of discomfort, uncertainty, mental stress, functional disorders, of fear, and conflictness as a response to the absence of a medicine that caused addiction. Drug allergy is an acquired unnatural reaction of the organism to medicines that appears after their repeated intake (on the 7th-12th day from the beginning of administration). Sensibilization is the process of the organism’s sensitivity increase to a medicine. Some medicines interacting with form complexes (haptens) and become true antigens. Drug idiosyncrasy is an inherited qualitatively unnatural reaction to a medicine appearing after the first contact with it. Dysbiosis (dysbacteriosis) is a disorder of the normal microflora content and development of non-typical microorganisms in the organism. The embryotoxic action appears on the early terms of (the first two weeks) and it is the result of the drug toxic action on the fertilized ovule at first, and then on the embryo. Often the embryotoxic action of medicines ends by the spontaneous abortion. If the embryotoxic effect does not end with abortion, then it is the beginning of the teratogenic action. Anomalies of the development – the teratogenic (in Greek teratos is ―freak, deformity‖) action - develop from the 3rd up to the 10th week of pregnancy when differentiation of the fetus tissues occurs most intensively; and because of this the most severe defects of fetus development occur. Functional and structural disorders of the fetus organs under the influence of drugs, which are capable to penetrate through the placenta in the IIIrd trimester of pregnancy, are called the fetotoxic action. The mutagenic action is the drug’s teratogenic effect fixed firmly in the genes, it arises more often when a woman and sometimes a man takes a medicine during a period of gonadogenesis. The blastomagenic (cancerogenic) action is the ability of a medicine to stimulate the development of tumors. Withdrawal syndrome (the exacerbation of the disease) develops with a long-term application of a medicine and then its sudden withdrawal.

PRINCIPLES OF THE DRUG DOSING

Dose (in Greek dosis is ―a portion‖) is the amount of a medicine that has come into the organism. It is usually expressed in gram or gram parts. Drugs doses, which are used for treating and do not cause pathological deviations in the organism’s vital activity, are called curative or therapeutic doses. A therapeutic dose is subdivided into single, daily and a course dose. A single dose is prescribed for one intake, a daily one is for the whole day and a course dose is taken the whole course of treatment. These doses are subdivided into minimal, average, maximal doses respectively. The minimal therapeutic dose (threshold) causes the minimal therapeutic effect; it is in 2-3 times smaller than the average therapeutic dose. The average therapeutic dose causes the optimal therapeutic effect in most patients without any toxic manifestations. The produces an average

10 therapeutic dose of a medicine in one unit of a medicinal form (in one ampoule, tablet), as a rule. The maximal therapeutic dose causes the most powerful therapeutic effect. A minimal dose, which causes side effects, is called minimal toxic. The minimal lethal dose (fatal) is called a minimal dose that causes death. The principle of dosing for chemotherapeutic medicines and cardiac glycosides differs from those for the other drugs. At first a loading dose is prescribed with the aim of creating a high concentration of a medicine in blood and tissues to obtain a fast therapeutic effect. And then a maintaining dose, which equals the amount of the excreted medicine during the time between intakes, is introduced. In medical practice only those doses of medicines that are in the range from the minimal therapeutic to the minimal toxic dose can be used. This interval is called the range of the drug therapeutic action. The more width the therapeutic action has, the safer a medicine is. To characterize the drugs’ safety the therapeutic value (TV) is also used. The therapeutic value is a ratio of an average lethal dose to an average therapeutic one: TV=LD50/ED50, where LD50 is a dose causing death of 50% of the experimental animals; ED50 is a dose that results in the pharmacological effect of 50% of the animals. The more therapeutic value is, the safer a medicine is.

THE ROUTES OF DRUG ADMINISTRATION

All routes of drug administration can be conditionally divided into ones used as the local action and others used as the resorptive action. The local administration of medicines has the aim of the long-term action in the site of application. Medicines are used locally in pathological processes on skin, the mucous membrane of eyes, nose, , urinary bladder and pleura. Hydrophilic substances (sugar, ions) are not absorbed by the skin and act surfactantly, and lipophilic substances ( , etc.) penetrate through the skin proportionally to their solubility in fats. The routes of drug administration with the aim of the resorptive action are divided into enteral and parenteral. The enteral route of drug administration through the gastrointestinal tract (ento means ―deep into‖, enteron is ―intestine‖) includes their intake sub linguam – under the tongue, sublingually; per rectum - through the rectum, rectally; per os – through the mouth, orally, perorally. These routes are given according to the onset of the drug action in the organism. The fastest onset of the drug action is when introducing them sublingually. The parenteral route is the introduction of medicines without getting into the gastrointestinal tract. By the increase of the drug action onset routes can be arranged as follows: subcutaneous, intramuscular, inhalant, intravenous and intra-arterial one. A positive aspect in the drug’s peroral administration is that it is the most suitable route, which does not require special equipment, sterility, participation of the medical staff and appliances. Liquid and solid medicinal forms can be taken by this way. The presence of the ―biological filtration‖ provides a rare appearance of drug negative effects. The most favourable time for internal intake of medicines is 30-40 minutes before meals or in 3-4 hours after meals. The main disadvantage of this route of drug administration is the fact that many medicines inactivate in the gastrointestinal tract interacting with food, enzymes and the

11 hydrochloric acid. (insulin, heparin, etc.) are not prescribed perorally as they are disintegrated in the gastrointestinal tract. This route is unsuitable for rendering a rapid aid (the occurs slowly). In the pathological states of the gastrointestinal tract the onset and the complete absorption of medicines change. All medicines absorbed in the gastrointestinal tract get into the , where they undergo chemical transformations and inactivation. The peroral route is unsuitable for reaching the accurate drug concentration in blood. The doses of medicines when taken them internally should be much more greater than when introducing them parenterally. Medicines are introduced via the rectum in the case when it is impossible to take them per os: in the unconscious state of a patient, while vomiting, in gastric diseases, to patients with mental disorders, as well as if a substance is destroyed quickly while passing through the liver. The rectal route of drug administration remains one of the rational routes in the pediatric practice. By onset of the effect this route is similar to the intramuscular one; in this case effect appears in 5-15 minutes. And medicines are destroyed in the liver not so rapidly, because from the rectum they come into blood, not through the portal vein, but via the postcava system, where up to 50% of the introduced dose does not get to the liver. With this route of introduction medicines have the biological filtration and their negative effect on the liver is decreased. The dose of medicines introducing through the rectum is more accurate, and it can be reduced in one third comparing to the peroral route of administration. Disadvantages of this route are discomfort of taking a medicinal form (suppositories, enema 40-45 ml), as well as the fact that not all substances are absorbed. Some medicinal substances are absorbed especially well from the sublingual area. When introducing medicines sublingually and behind the cheek (subbucally) they act rapidly (the effect develops in 1-3 minutes), avoid the liver barrier, do not interact with the hydrochloric acid and enzymes of the gastrointestinal tract. This route of administration can be used mainly for strong effective medicines, as well as for medicines that are destroyed by gastrointestinal enzymes. The parenteral route of drug administration has the advantage over the enteral one: a medicine gets into blood (accurate dosing) more rapidly and completely; a possible introduction of medicines to the unconscious patient, medicines are not destroyed in the liver and the gastrointestinal tract. The negative features of the parenteral route of drug introduction are the necessity of keeping the strict aseptics, participation of the medical staff, the presence of instruments, the risk of the organism’s contamination, injuries while introducing a medicine. Aqueous and oil () solutions of medicines, suspensions (the prolonged forms of insulin) are introduced subcutaneously. The intramuscular route of drug administration provides their coming into the general blood circulation in 10-15 minutes. Due to a good blood supply the muscular tissue absorption of medicines into the blood occurs rather fast. Medicines that are absorbed well through the mucous membrane of alveoli and possess the systemic action are used in the form of inhalations (remedies for inhalation narcosis). The intravenous route of drug introduction is used in the emergency cases when very rapid onset of action is necessary to reach the required effect. It is forbidden to introduce oil solutions, suspensions, medicines causing hemolysis, thrombosis, conversion

12 of hemoglobin into methemoglobin, containing air into the vein. The introduction of the medicines with the irritative properties in the vein can result in the development of phlebitis. Medicines that penetrate through the blood-brain (haematoencephal) barrier poorly are introduced under the membranes of the brain – subarachnoidly and subdurally ( in the cases of infectious diseases of the brain tissues). In order to avoid or reduce the negative effect of medicines physicians and pharmaceutists should always remember that the right choice of a dose, the route of drug administration, simultaneous administration of etiotropic, pathogenetic and symptomatic therapy are the important conditions for successful pharmacotherapy of any disease.

PHARMACOKINETICS OF MEDICINES

The (pharmakon means ―medicine‖, kinetikos is ―motion‖) studies transport (absorption), distribution (deposition), transformation (biotransformation, ) of medicines and their excretion (elimination) from the organism.

Fig. 1. Steps of pharmacokinetics

Absorption of medicines The process of drug absorption from the gastrointestinal tract, via skin, the respiratory system organs and the vessels’ wall is mainly provided by 4 types of the biological membranes as processes of the passive diffusion, the facilitated diffusion, the active diffusion and pinocytosis. The passive diffusion is characterized by such features as: a) molecules of a medicine move from the area with a high concentration to the area with a low concentration; b) the rate of transport is proportional to the concentration gradient on the both sides of the membrane. Membranes of the second type (facilitated diffusion) contain substances – specific carriers that provide the transport for particular medicines only. This transport occurs by the concentration gradient and is not connected with the energy loss, and the rate of this diffusion is high. In the membranes of the third type the drug absorption takes place by the active diffusion with the consumption of energy. Here transport can occur against

13 the concentration gradient. It is provided by the presence of a carrier, which changes its structure during the transport of a drug , and this process requires the consumption of energy. This mechanism is called the biological pump. The essence of pinocytosis process, absorption of medicines by the fourth type membranes, is in that substance, which is being carried, contacts with a definite part of the cells’ membrane surface and this section sags inwards, the edges of the hollow closes forming a bubble with the substance transported. It separates from the outer surface of the membrane and is transferred into the cell. The fourth type membranes are located in the renal glomeruli. The first type membranes with some areas of the membranes of the second and the third type are functioning in the renal tubules. The first type membranes are mainly in the gastrointestinal tract. Capillaries possess the properties of the first type membranes containing some areas with the fourth type membranes. During absorption medicines get over the histohematic, blood-brain and placental barriers. The blood-brain barrier (BBB) is the membranes that separate the cerebral tissue and the cerebrospinal liquid from blood. The ability of medicines to pass the blood-brain barrier depends on their solubility in fats. If a substance is soluble in fats, it penetrates quickly into the brain and the cerebrospinal liquid. Because of children of the younger age have an incomplete BBB comparing to the adult’s BBB, medicines pass it much faster. The placental barrier separates the blood circulation of the mother and the fetus. It has a high permeability (erythrocytes penetrate through it) at the early stages of pregnancy, then it strengthens and acquires all the features of the lipoid membrane with the active transport of metabolites. The placental permeability increases in the period of toxicosis, at early stages of pregnancy, in hypoxia, hemorrhage, endocrine dysfunctions. Those substances, which in the normal conditions do not cross the placental barrier, can penetrate through it in these cases. The penetration of medicines through the placental barrier is the cause of their negative (teratogenic) effect on the fetus.

The distribution of medicines in the organism The drug distribution in the organism depends on its ability to bind with the ingredients of blood or other tissues. It leads to the drug deposition. Binding of a medicine to proteins limits its distribution in the organism because only the free form of a medicine can diffuse through the biological membranes. There are three fractions of medicines: free, bound with proteins, fixed in tissues. Only free fraction possesses the pharmacological effect and undergoes biotransformation and excretion. The process of drug binding influences considerably on revealing their specific activity. A high level of binding substances to proteins stipulates their prolonged effect (sulphadimethoxin). The peculiarity of the drug distribution is determined by their ability to dissolve in water or lipids. Medicines distribute faster in organs with the intensive blood flow (heart, liver, kidneys) and this process is much slower in tissues with a relatively low blood flow (subcutaneous cellular tissue, adipose and

14 tissue). When the blood supply of the internal organs becomes worse, the distribution and effectiveness of medicines decrease too. Fats, proteins and mucopolysaccharides play the main role in depositing of medicines. Binding of medicines to proteins can decrease in the diseases of liver, kidneys, as well as in sepsis, burns, gastritis, enteritis, gastric ulcer, protein starvation or during the simultaneous administration of some medicines.

The biotransformation of medicines

(The main ways of the ) Biotransformation is the process of utilization, transformation of a medicine into metabolites that are dissolved well in water and excreted by kidneys. The importance of the biotransformation is in transformation of a foreign medicine potentially dangerous for the organism (xenobiotics) into a water soluble compound that eliminates fast from the organism. That is why the main aim of the biotransformation is the transformation of lipophilic substances (easily reabsorbed in the renal tubules) into the hydrophilic polar compounds that are easily excreted by kidneys (not reabsorbed in the renal tubules). Metabolites can be excreted from the organism or undergo further transformations. The biotransformation of medicines proceeds in 90-95% in the liver cells (in their microsomes that contain the sets of enzymes required for the drug metabolism), as well as in the intestine, lungs, kidneys, blood and placenta. The processes of the drug metabolism are conditionally divided into two phases. A drug molecule transforms forming the functional groups with the active atoms: oxy-, amino-, carboxy-groups, etc. in the first phase owing to oxidation, reduction or . The conjugation to highly polar acid residues of the glucuronic, sulphuric and some aminoacids occurs in the second phase with the participation of these functional groups. As a rule, the biotransformation leads to the decrease of the pharmacological activity (inactivation) of medicines. However, in a number of cases the formation of the active metabolites can take place. First of all, it concerns the precursors of medicines – , which become active in the process of metabolism. In some cases in the process of the drug metabolism toxic metabolites are formed. This phenomenon is called the “lethal synthesis”. The drug metabolism determines the time of the drug circulation in the organism and, as a consequence, the duration of the therapeutic effect and the scheme frequency of usage of a drug dosing as well. The rate of the drug biotransformation depends on the activity of enzymes metabolizing them, age and the state of the organism, simultaneous administration of other medicines. The rate of the drug metabolism is determined by the genetic factors. Pharmacogenetics is the part of pharmacology, which studies the congenital peculiarities of enzymes that metabolize medicines in humans. The damage of the structure and the function of the metabolizing enzymes is called enzymopathy (the defect). The phenomenon of induction and inhibition of metabolizing (microsomal) enzymes affects the rate of a drug metabolic transformation. There are about 250

15 substances known, which are capable to cause induction of metabolizing enzymes (e.g., ). While using these medicines the effectiveness of those medicines, biotransformation of which occurs with the help of cytochrome P-450, is especially decreased. The induction of metabolic enzymes is a reversible process. The enzymatic activity decreases reaching the initial level in the period of time after the inducers stop their coming into the organism. The inhibitors of cytochrome P-450 include salts of heavy metals, chloramphenicol, metronidazole, oleandomycine, , tetracycline, erythromycine, , etc. It is necessary to correct the doses of medicines in case of their simultaneous administration with inductors or inhibitors of the microsomal liver enzymes.

The elimination of medicines from the organism Elimination is the process of removing a medicine from the organism by biotransformation and/or excretion. The main way of the drug excretion in the unchanged state or as metabolites is their elimination with and faeces. Besides, medicines can be eliminated from the organism with the exhaled air, with the secret of the mammary, perspiratory and salivary glands. To estimate the elimination rate with urine a special parameter is used. It is the renal clearance (Clren), which determines the amount of plasma (serum) being cleaned by kidneys from a medicine for a unit of time. Medicines not absorbed in the intestine (Phthalazole, sulphate) are eliminated with faeces. The information about the pharmacokinetic parameters of medicines stipulates the scheme of their administration and supporting of their concentration in blood in the therapeutic level, which is especially important for medicines with a low range of the therapeutic action.

THE COMBINED ADMINISTRATION OF MEDICINES

Medicines are combined for decreasing or removing undesirable effects of pharmacotherapy, increasing the therapeutic effect or reducing the period of treatment. Such types of the as pharmaceutical, pharmacokinetic and pharmacodynamic interactions can be observed in case of combined administration of medicines. The pharmaceutical interaction is based on physical, physical-chemical and chemical reactions of medicinal substances, which are in the composition of one medicinal form, or which appear with their simultaneous administration. The pharmacokinetic interaction of medicines is revealed at the stages of their absorption, transport, distribution, biotransformation and excretion. The pharmacodynamic interaction is observed when with drugs simultaneous administration the changes of their pharmacological effects appear as a result of their effect upon the specific receptors, cells, organs and systems. The result of this interaction is decrease or disappearance of the effect, distortion of the drug action or increase of the effect up to the development of toxic phenomena.

16 If two medicines act in the same direction, such an interaction is called synergism (in Greek synergos is ―acting together‖). It is displayed in 3 forms: additive, summarized (direct) and potentiated (indirect). In the additive synergism the pharmacologic effect of the combination is higher than that of one of the components, but less than their sum is (1+1=1.75); in the summarized synergism the effect of the combination is equal to the arithmetic sum of the monodrugs effects (1+1=2); in the potentiated synergism (from English ―to potentiate‖) the total effect exceeds the sum of drug effects (1+1=3). The summarized action is observed in the direct synergism: medicinal substances affect the same receptors (e.g., noradrenaline and ). Potentiation is typical for the indirect synergism when substances have different mechanisms of action and affect different receptors. The synergism phenomenon is used for obtaining the desired therapeutic effect while taking smaller doses of medicines; it decreases the possibility of their side effect. If the effects of a medicine decrease or disappear while interacting with another one, this phenomenon is called antagonism (in Greek anti means ―against‖ and agon is ―struggle‖). Antagonism is widely used to remove the negative effects of medicines, as well as in poisonings. There is physical, chemical and functional antagonism. The physical antagonism is observed in the absorption of different toxic substances by adsorbents (the activated carbon absorbs different toxins on its surface). In the chemical antagonism inactive substances appear as a result of chemical reactions (the interaction of alkalies and acids). The functional antagonism is a phenomenon when medicinal substances affect the same receptors, but in the opposite directions (cholinomimetics and cholinoblockers). Medicines used to remove the effects of other substances when poisoning are called antidotes.

FACTORS AFFECTING THE DRUG PHARMACOKINETICS AND PHARMACODYNAMICS

All the factors that can affect the drug pharmacokinetics and pharmacodynamics can be divided into exo- and endogenous factors. The chemical structure and physical properties of a medicine, medicinal form, the route of its administration and a dose, the scheme of nutrition, the composition of food, the state of the environment (the circadian rhythms, the atmospheric pressure, temperature of the air), etc. belong to the exogenous factors, which are not related to the patient’s organism. The endogenous factors connected with the patient’s organism are the body weight, sex, age, the physiological (pregnancy, lactation, climacterium, hypodynamia, the body temperature) and the pathological (diseases of the thyroid gland and the gastrointestinal tract, alcoholism) state of the organism. One of the leading endogenous factors determining the success of the therapy is age. It is connected with the fact that the level of the biochemical processes functioning differs in different age periods. The geriatric pharmacology studies the peculiarities of the drug action in elderly people and the pediatric pharmacology deals with the same problems in children.

17 PARTICULAR PHARMACOLOGY (A guarantee to become a physician or pharmaceutist)

I. MEDICINES AFFECTING AFFERENT INNERVATION

ASTRINGENT, COATING, ADSORBENT, AGENTS and MEDICINES CONTAINING VOLATILE OILS are medications that increase or decrease excitability and conductivity of the afferent nerves.

Classification of medicines Local , expectorants, , bitters - see other chapters Astringentº, coating*, antacid** Adsorbents Containing volatile oils agents Of plant origin: Salts of metals: Activated Oak barkº Aluminium carbon Espol Sage leavesº phosphate*\** Enterosgel seeds Chamomile Colloidal bismuth Diosmectit Menthol in flowersº subcitrateº\** bromisovalerianate Tanninº Almagel*\** Vicalinº\** Anacid*\**

The mechanism of action These medicines coat the afferent nerve endings forming colloid solutions (aluminium phosphate, almagel, anacid, enterosgel) in water; neutralize the free HCl of the gastric juice (aluminium phosphate, almagel, anacid); cause precipitation of proteins forming albuminates that make a film-like cover and protect receptors of the skin or the mucous membrane of the gastrointestinal tract (colloidal bismuth subcitrate, vicalin, plant astringents); adsorb chemical substances on their surface (anacid, adsorbents). Volatile oils irritate the afferent nerve endings and dilate arterioles and capillaries by reflex.

Pharmacodynamics (effects) → Indications Coating and gastro-protective (salts Inflammatory diseases of the of metals); antacid (); gastrointestinal tract: enterites, gastrites, , astringent, anti- peptic ulcer, etc. inflammatory and antiseptic (plant origin ones) Astringent, anti-inflammatory, Catarrhal-inflammatory diseases: tonsillitis antiseptic, sudorific, wound healing (fauces), laryngitis (vocal cords), (plant origin agents) (throat). Inflammatory diseases of the gum (stomatitis), vagina, uterine cervix and the skin. Decubituses, ulcers, intertrigoes, dermatites, erosions, diatheses Adsorptive (adsorbents) Poisonings by , food. Enterosorption. Diarrhea

18 Local irritants (espol, mustard seeds) Arthrites, myosites, rheumatism, radiculitis, myalgia Astringent, gastro-protective, Food poisonings antiseptic (plant origin agents) , spasmolytic (menthol, , angina pectoris validol) Side effects → Contraindications Constipation or diarrhea, skin irritation Skin irritation (for the local-acting ones)

The list of medicines INN, (Trade name) Medicinal form, dosage Activated carbon (Carbolen) Pwd, tabl. 0.5 Almagel Susp. per os Aluminium phosphate Gel 16.0 Anacid Susp. per os Chamomile flowers Pack 100.0 Colloidal bismuth subcitrate (De-nol) Tabl. 0.12 Diosmectit (Smecta) Pwd., package 3.0 Enterosgel Gel, pack Espol Ointment, tube Menthol Oil sol. 1% Menthol in bromisovalerianate Tabl. 0.06 Mustard seeds (Mustard paper) Package Oak bark Pack 100.0 Sage leaf Pack 100.0 Tannin Pwd, package Vicalin Tabl.

Glossary Enterosorption is the introduction of a sorbent in the gastrointestinal tract. Diarrhea is a loose stool. Migraine: its main symptom is a strong headache.

LOCAL ANESTHETICS

Local anesthetics are medicines causing the local reversible loss of pain and other kinds of sensibility in the site of introduction.

Classification of medicines

Para- Benzofurocarboxylic Substituted amides of aminobenzoic acid derivatives acid Procaine Benzofurocaine Articaine Trimecaine hydrochloride

19 The mechanism of action Due to the membrane stabilizing effect local anesthetics reduce the membrane permeability for different ions (Na+, K+), inhibit the release of neurotransmitters. It leads to the change of the bioelectric potential on the cell membrane and disturbs the transfer of the nervous impulses through synapses.

Pharmacodynamics (effects) → Indications Different types of the local Side effects → Contraindications , convulsions, disorders in the cardiac Hypotension, , conduction system arrhythmia

There is the latent period, which exists from the moment of introducing a local anesthetic till the development of the local anesthetic effect. That is why it is necessary to wait for the beginning of the drug action and do not administrate the medicine repeatedly, as it can lead to intoxication. Vasoconstrictive medicines potentiate and prolong the effect of local anesthetics.

The pharmacological “face” of local anesthetics Effect Anes- Perme- Toxi- Medicines antiar- hypoten- central thesia ability city rhythmic sive Procaine + ++ ± + + Benzocaine + ± Benzofuro- ++ +++ ± + caine Articaine + + Lidocaine ++ +++ ++ + + Trimecaine ++ +++ +

The list of medicines INN, (Trade name) Medicinal form, dosage Articaine (Ultracaine) Sol. for inj. 1% Benzofurocaine Aer. 50.0 Benzocaine (Anesthesine) Sol. for inj.1% Lidocaine Sol. for inj. 1%; gel 2.5% Procaine (Novocaine) Sol. for inj.1%; oint. 10% Trimecaine hydrochloride Sol. for inj.1%

Glossary Local anesthesia is a temporary, reversible loss of all kinds of sensibility (pain, temperature, tactile) only in the site of the drug introduction without impairment of consciousness. Main types of the local anesthesia are surface (terminal) (in the site of application), conduction (by the nerve fibre) and infiltration (soaking of a tissue by anesthetics layer-by-layer) anesthesia.

20 II. MEDICINES AFFECTING EFFERENT INNERVATION Normal functions of the efferent nerves are provided by such neurotransmitters (mediators) as , noradrenaline, adrenaline, dophamine. Medicines, which action is similar or opposite to these neurotransmitters, are widely used for the pharmacological correction of functional disorders of different organs and they are called medicines of the mediator action or mainly affecting the efferent division of the (efferent innervation). As these medicines change the rate of the nervous impulse conductivity in synapse, they are also called synaptic-acting medicines. Synapse is the place of action for the drugs primary influencing on the peripheral processes of neurotransmission (the efferent section of the nervous system). In order to conceive clearly the localization, the mechanism of action and pharmacodynamics of medicines influencing selectively on the efferent section, it is necessary to know physiological and biochemical peculiarities of the efferent section, its role in the functions of the whole nervous system. The efferent section of the nervous system is presented by nerves- ―executors‖ (centrifugal), unlike the afferent section that includes sensible nerves (centripetal). The efferent nerves are divided into motor (somatic) and vegetative (autonomic). The latter are divided into the parasympathetic and sympathetic nerves. The motor nerves do not break, and the vegetative nerves break in ganglia. Ganglion (the cluster of neurons) is the multiplying apparatus of the nervous system due to it the CNS provides regulation of functions for the whole organism. Synaptic contacts of one neuron and another occur in ganglia. The structural unit of the nervous tissue – neuron - joins another neuron or a cell of the internal (working) organ in synapse (from Latin ―close down‖). There are the following structural elements in synapse: 1. A presynaptic membrane (the axon’s ending) contains a neurotransmitter (neuromediator), which is formed in the neuron’s mitochondrion and accumulates in the axon’s vesicles (bubbles) in the inactive state. Acetylcholine and noradrenaline are the main neurotransmitters in the excitation transfer in the peripheral nerve endings. 2. A postsynaptic membrane (the dendrite ending or the cell membrane of the working organ) contains M- and N-cholinoreceptors (ChR), α- and β- adrenoreceptors (AR). They are sensitive to the corresponding mediators, as well as cations (Na+ and K+) and anions (Cl-, organic acids), which create the potential difference on the postsynaptic membrane. 3. The synaptic cleft is area, where such enzymes as inactivating acetylcholine (ACh), MAO and COMT (monoamine oxidase and catechol-o-methyltransferase) enzymes, inactivating noradrenaline and adrenaline, are secreted. Besides, for example, , which is formed after acetylcholine breakdown, undergoes the recapture (re-uptake) by the presynaptic membrane. To transmit the nervous impulse from one neuron to another (or on the working organ), synapse must pass through three states: polarization → depolarization → repolarization.

21 Polarization (the state of rest) is characterized by the presence of neurotransmitters (mediators) in the inactive state in vesicles, receptors of the postsynaptic membrane are not excited and it is impermeable for Na + and K+. Depolarization is the state when under the nervous impulse stimulation a mediator releases into the synaptic cleft by portions and reaches receptors in milliseconds. The configuration of receptors changes because of their interaction with mediators and the ion canals open; along them Na+ ions go into the cell, and K+ ions come out of the cell. The action potential and the membrane polarization phase appear. Repolarization is the state when an enzyme inactivates the part of a mediator, and the unbroken part of the latter is captured by the presynaptic membrane. Sodium is displaced out of the cell and potassium returns into the cell with the help of the membrane’s sodium-potassium pump. The membrane repolarization, i.e. the reconstruction of the initial state (polarization), takes place. The mediator ACh stimulates M- and N-cholinoreceptors. Depending on their sensitivity to definite compounds ChR are divided into M-ChR (they are also stimulated by muscarine – , poison of fly-agaric mushrooms) and N-ChR (they are also stimulated by – alkaloid of leaves). Noradrenaline (NA) (mediator) and adrenaline () stimulate AR. M-ChR and AR are located mainly in organs, N-ChR are in the skeletal muscles, ganglia, the carotid sinus and the adrenal medulla; all ChR and AR are also found in the CNS. Synapses and nerves, where the nervous impulse transfer occurs with the help of ACh, are called . Motor, parasympathetic, preganglionic sympathetic nerves, postganglionic sympathetic innervating sweat glands, skeletal muscles vessels, the adrenal medulla and the carotid sinus belong to cholinergic nerves. Postganglionic sympathetic nerves, excluding innervating sweat glands, vessels of the skeletal muscles, the adrenal medulla and the carotid sinus belong to adrenergic nerves.

Classification of medicines affecting efferent innervation I. Cholinergic (the action is similar to acetylcholine functions) medicines. II. (the action is opposite to acetylcholine functions) agents. Medicines block ChR and make them insensitive to a neurotransmitter. III. Adrenergic (their action is similar to noradrenaline and adrenaline functions) medicines. IV. Anti-adrenergic (opposite to adrenergic agents) medicines.

Comparing the classification and the effects of these medicines it can be conditionally considered that when using of cholinergic medicines the effects connected with the stimulation of parasympathetic nerves dominate in the organism, while with adrenergic medicines sympathetic nerves are stimulated. Therefore, to understand pharmacodynamics of the medicines affecting efferent innervation, particularly, autonomic nervous system it is necessary to know the basic effects occurring in organs when parasympathetic or sympathetic nerves are stimulated.

22 Table 1 The influence of the parasympathetic and sympathetic nervous system on the organs’ functions Organ Effects under the nerves stimulation Parasympathetic Sympathetic Eye Constriction of pupil Dilation of pupil (mydriasis), (myosis), IOP decrease IOP increase (↑), (↓), accommodation accommodation paralysis spasm (myopia) (hyperopia) Exocrine glands (sali- The secretion increase The secretion decrease vary, lacrimal, etc.) Bronchi Spasm Dilation Heart Rhythm ↓ (bradycardia), Rhythm ↑ (tachycardia), contractility ↓ contractility ↑ GIT Acceleration of peristalsis Deceleration of peristalsis Sphincters Relaxation Spasm Urinary bladder Increase of the urine Decrease of the urine secretion (tone ↑) secretion (tone ↓) Uterus Contractility and tone ↑ Contractility and tone ↓ Vessels Vessels dilation, BP ↓ Vessels spasm, BP ↑

CHOLINERGIC MEDICINES (CHOLINOMIMETICS, CHOLINERGIC AGONISTS) By the mechanism of action this group of medicines is divided into direct- acting cholinomimetics (from English ―to mimic‖) and indirect-acting cholinomimetics (anticholinesterase agents).

DIRECT-ACTING CHOLINOMIMETICS

Classification of medicines M-, N-cholinomimetics M-cholinomimetics N-cholinomimetics Acetylcholine Pilocarpine Carbacholine Aceclidine

The mechanism of action M-cholinomimetics stimulate M-ChR, N-cholinomimetics stimulate N-ChR, M- and N-cholinomimetics stimulate both M- and N-ChR. Binding to the corresponding receptors these medicines provide effects, which are similar to the effects of the endogenous ligand, i.e. they act as agonists of ACh.

Pharmacodynamics (effects) → Indications Local action: IOP decrease, myosis, the Glaucoma (except N- accommodation spasm cholinomimetics) Resorptive action: increase of the smooth muscles Atony of the GIT, uterus, tone of the GIT, uterus, gall and urinary bladder, urinary bladder; radiography increase of the exocrine glands secretion; reflex of the GIT (except N- stimulation of the respiratory centre (stimulation of cholinomimetics). Asphyxia the carotid sinus N-ChR) (N-cholinomimetics only)

23 Side effects → Contraindications BP decrease, bradycardia, bronchospasm Hypotension, bradycardia, bronchial (BA)

The pharmacological “face” of direct-acting cholinomimetics Medicines Action Peculiarities Strength Duration Resorptive Local Acetylcholine + + + - not introduced iv Carbacholine ++ ++ + + Pilocarpine + + - + toxic Aceclydine ++ ++ + + Cytisine ++ + + - ↑ respiration Lobeline ++ + + - ↑ BP

The list of medicines INN, (Trade name) Medicinal form, dosage Aceclydine Sol. for inj. 0.02% Acetylcholine Pwd. for inj. 0.2 Carbacholine () Sol. 3% Cytisine (Cytiton, Tabex) Sol. for inj. 0.15%; tabl. 0.0015 Lobeline Sol. for inj. 1% Pilocarpine Sol. 1%

Glossary Agonist is a medicine that while binding to receptors causes effects similar to the effects of the corresponding mediator. Atony (atonia) is the absence of the muscle tone. Intraocular pressure (IOP) is the pressure of the intraocular liquid in the eye cavity. Hypotension is the BP decrease. Glaucoma is the eye disease, its main feature is the IOP increase. The carotid sinus is the sinus of the carotid artery. Myosis is the pupil’s constriction. Accommodation spasm (myopia) is the vision of objects located near-by. Endogenous ligands are endogenous substances that bind to the receptors or other formations of the organism.

INDIRECT-ACTING CHOLINOMIMETICS (Anticholinesterase medicines)

Anticholinesterase medicines are medicines that inhibit acetylcholinesterase enzyme and, thus, increase the acetylcholine concentration in the synaptic cleft.

Classification of medicines Reversible- and irreversible*-acting anticholinesterase medicines Physostigmine Galanthamine Neostigmine methylsulphate Armine*

The mechanism of action Anticholinesterase medicines block (reversibly or irreversibly) the acetylcholinesterase enzyme that leads to increase of the ACh content in the synaptic cleft and stimulation of the postsynaptic M- and N-ChR (ACh is a common mediator for them). While taking these medicines the effects of the parasympathetic nerve

24 system prevail and that is why the effects of these medicines are similar to the effects of ACh and direct-acting cholinomimetics.

Pharmacodynamics (effects) → Indications M-cholinomimetic: Glaucoma. Paresis and paralysis of the -decrease of the IOP, myosis, the intestine (more often after operations on accommodation spasm; the abdominal cavity organs), atony of -increase of the smooth muscle, tone of the urinary bladder, the uterine inertia organs N-cholinomimetic: Myasthenia. Postsymptoms after polio- -relief of the neurotransmission through myelitis and dysfunction of the cerebral the neuromuscular synapses; circulation, neuritis -improvement of the neuromuscular conductivity M- and N- cholinomimetics: As antidotes in poisoning by non- depolarizing myorelaxants, M-cholino- blockers Side effects → Contraindications Bronchospasm, bradycardia, BP Bronchitis, BA, severe heart diseases, decrease, convulsive reactions bradycardia, hypotension, epilepsy

The pharmacological “face” of indirect-acting cholinomimetics Medicines Action Side Strength Duration Resorptive Local effects Galanthamine + ++ + - + Physostigmine + + + + ++ Neostigmine ++ + + + ++ Armine* +++* +++* - + +++ *- in glaucoma only.

The list of medicines INN, (Trade name) Medicinal form, dosage Armine Sol. 0.01% Galanthamine (Nivalin) Sol. for inj. 1% Neostigmine methylsulphate (Proserin) Sol. for inj. 0.05% Physostigmine (Eserin) Sol for inj. 0.1%

Glossary Myasthenia is the disease when the tone is absent partially or completely. Neuritis is the inflammation of nerves. Paralysis is the absence of the voluntary movements because of the muscle innervation disorder. Paresis is decrease of muscular sensitivity and force due to disorders of neurotransmission. Poliomyelitis is the acute infectious viral disease accompanied by paresis and paralysis of the extremities.

25 ANTICHOLINERGIC MEDICINES (CHOLINOBLOCKERS, CHOLINERGIC ANTAGONISTS)

Anticholinergic medicines block ChR selectively being competitive antagonists of the ACh mediator and cholinomimetics. According to their action on the receptors they are divided into M-cholinoblockers and N-cholinoblockers.

M-cholinoblockers Classification of medicines Ones of plant origin Synthetic ones sulphate Ipratropium Homatropine hydrobromide Methacine iodide Platyphyllin hydrotartrate Pirenzepine hydrochloride Tropicamide The mechanism of action Medicines of this group block M-ChR of organs reversibly and selectively, thus, they stop the impulse transmission from the postganglionic parasympathetic nerve endings to the internal organs cells stipulating the prevalence of the sympathetic innervation effects. At present because of the M-ChR (M1-M5) subtypes identification medicines, which act selectively on different M-ChR subtypes have appeared. Pirenzepine blocking selectively M1-ChR of the stomach mucous membrane belongs to selective M1-cholinoblockers. Pharmacodynamics (effects) → Indications The dilation of pupil (mydriasis), Diagnosis of the eye diseases, inflammatory IOP↑, accommodation paralysis eye diseases Inhibition of the exocrine glands BA, peptic ulcer, gastritis, anesthesiology secretion, the smooth muscles (the prophylaxis of bronchospasm), colics relaxation (in case of the spasm) of organs Tachycardia Bradycardia, prophylaxis of heart stoppage Side effects → Contraindications Accommodation paralysis, IOP↑, Bradycardia, glaucoma, atony of the GIT, intestinal peristalsis ↓, dry mouth, tachycardia tachycardia Atropine sulphate (alkaloid from the Solanaceae family plants) is the reference drug of this group. The effects of atropine sulphate and similar medicines are opposite to the effects of cholinomimetics.

The pharmacological “face” of M-cholinoblockers Medicines Action Peculiarities Strength Duration Re- Lo- Spas- sorp- cal mo- tive lytic • Atropine A (refe- 8 days + + +++ ↓ M1-ChR (of the sulphate rence) stomach), M2-ChR (of the heart), M3- ChR (of the eyes)

26 • Homatropine

The list of medicines INN, (Trade name) Medicinal form, dosage Atropine sulphate Sol. for inj. 0.1%; sol. 1% Homatropine hydrobromide Sol. 0.25% Ipratropium bromide (Atrovent, Rinatec) Sol. for inhalation 0.025%; aer. 0.05% Methacine iodide Sol. for inj. 0.1%; tabl. 0.002 Pirenzepine (Gastrocepine) Sol. for inj. 0.5%; tabl. 0.005 Platyphyllin hydrotartrate Sol. for inj. 0.2%; tabl. 0.005 Scopolamine hydrochloride Sol. for inj. 5% Tropicamide (Midriacyl) Sol. for inj. 0.5%

Glossary Accommodation paralysis is the vision of objects located at distance (hyperopia).

N-Cholinoblockers N-ChR are located in the ganglia of the autonomic nervous system, synapses of skeletal muscles, adrenal enterochromaffin tissue and the carotid sinus. N- cholinoblockers are different: some of them block N-ChR in ganglia, others act in the skeletal muscles. The former are called ganglionic blockers, which are used for stopping the impulse transmission through the autonomic ganglia, the latter are muscle relaxants applied for relaxation of the skeletal muscles.

Ganglionic blockers – N-ChBl is

Classification of medicines Tertiary* and quaternary -containing compounds Azamethonium bromide Dimecoline iodide Pachicarpine hydroiodide* benzosulphonate

27 The mechanism of action Ganglionic blockers are similar to ACh by their chemical structure. As a result of their competitive antagonism with ACh for N-ChR of the sympathetic and parasympathetic ganglia they block these receptors and interrupt the nervous impulse transmission through ganglia. While introducing ganglionic blockers the ―pharmacological denervation‖ of the internal organs occurs. Ganglionic blockers stopping the neurotransmission in ganglia act by the principle of breaking the interaction of the nervous centres and the effectory organs, and it results in the state of a relative rest of the latter.

Pharmacodynamics (effects) → Indications Dilation of arterial vessels and the BP Hypertension, the HC reduction, decrease (the postload on the myocardium artificial (controlled) hypotension in decreases), improvement of the blood the surgery of the vessels that is the circulation and microcirculation in the vessels most dangerous by vast , of the extremities surgery of heart and in neurosurgery Dilation of the venous vessels, decrease of Endarteritis, Raynaud's disease, the preload to the myocardium and the pressure pulmonary and brain edema in the pulmonary circulation Blockade of the cardiovascular reflexes both In surgery for decreasing the risk of pathological (for example, in shock, the shock development risk infarction) and compensatory ones Decrease of the gastric juice secretion, Ulcer of the stomach and motility and peristalsis of GIT organs duodenum, spastic colitis Stimulation of the uterine contractions and Labour induction (Pachicarpine tone hydroiodide) Side effects → Contraindications Tachycardia, orthostatic collapse, atony Myocardial infarction at the acute stage, of intestine and urinary bladder, IOP marked hypotension, atony of the stomach increase, dry mouth, dizziness and the intestine, glaucoma, pregnancy, (vertigo), general weakness atherosclerosis, thrombosis

The pharmacological “face” of Ganglionic blockers Medicines Effect Peculiarities of Strenth Duration administration Azamethonium bromide + + For cystoscopi in men Pachicarpine hydroiodide + ++ Increase of uterine tone, Dimecoline iodide +++ ++ BP  Hexamethonium benzosulphonate ++ + For HC

The list of medicines INN, (Trade name) Medicinal form, dosage Azamethonium bromide () Sol. for inj. 5% Dimecoline iodide (Dimecoline) Tabl. 0.025 Hexamethonium benzosulphonate (Benzohexonium) Tabl. 0.25; sol. for inj. 2.5% Pachicarpine hydroiodide Tabl. 0.1; sol. for inj. 3%

28

Glossary Raynaud's disease is spasms of fingers, hands and feet arteries, which turn pale, with pain and paresthesia. Hypertension is the chronic disease of the cardiovascular system characterized mainly by the stable increase of the BP. Hypertensive crisis (HC) is an acute exacerbation of hypertension. Orthostatic collapse is an acute decrease of the BP when the body position changes from horizontal to vertical one. Postload is the power that the heart needs to overcome the total peripheral vascular resistance of arteries to the blood stream. Preload is the pressure on the heart valves in the venous return of blood to the heart. Endarteritis is the spasm of the lower extremity arteries.

MUSCLE RELAXANTS

Muscle relaxants (myorelaxants) or -like medicines stop the impulses’ transmission from the motor (somatic) nerves to the skeletal muscles causing the relaxation of the skeletal muscles. The forefather of this group is considered to be curare, the arrow poison of the South-American Indians, it is the mixture of extracts from several species of tropical plants.

Classification of medicines Depolarizing agents Non-depolarizing agents Suxamethonium iodide Diplacine dichloride The mechanism of action By the mechanism of action muscle relaxants are divided into: 1. Antidepolarizing (non-depolarizing) agents (pachicurare). Medicines, which are competitive antagonists to ACh, block N-ChR in the postsynaptic membrane of the neuromuscular synapse and stop the appearance of the membrane depolarization and excitation (stimulatory impulse) of the muscle fibre. 2. Depolarizing agents (leptocurare). They are chemically similar to ACh and that is why they interact with N-ChR causing a prolonged depolarization of the postsynaptic membrane and, thus, they disturb the transmission of excitation from the nerve to the muscle.

Pharmacodynamics Myorelaxants cause relaxation of the skeletal muscles in a certain sequence. At first, the paralysis of small muscles of face, neck, fingers and toes and speaking disorders develop. Then the muscles of extremities, trunk, intercostal muscles, muscles of abdomen and, at last, diaphragm stop functioning consistently. But consciousness and sensitivity are not disturbed. Death can be caused by hypoxia (diaphragm and breathing muscles stop working). The recovery of the muscle tone occurs in the reverse order.

Indications Multicomponent narcosis (for stopping the physiological respiration and relaxation and performing the controlled ones). Setting of dislocations and reposition of bone fragments in fractures. Relief of convulsions.

29 NB! It is necessary to introduce muscle relaxants only after the intubation of a patient and his transferring to the artificial controlled respiration.

Side effects All non-depolarizing muscle relaxants are histamine liberators (stimulation of histamine release), so they can cause false allergic reactions (pseudoallergy), especially bronchospasm, the BP decrease. Suxamethonium iodide causes arrhythmia, apnoea, potassemia and the heart stoppage.

Contraindications Myasthenia, diseases of liver and kidneys, shock, early terms of pregnancy and elderly age. Suxamethonium iodide is contraindicated to children, in glaucoma, vertebral fractures, anemia, cachexia.

The pharmacological “face” of muscle relaxants Medicines Action It causes BP Strength Duration Bronchospasm Pseudo- allergy Suxamethonium + + - - - iodide Diplacine ++ ++ - + ↑ dichloride Tubocurarine +++ +++ + + ↓ chloride Pipecuronium ++++ +++ + + ↓ bromide

The list of medicines INN, (Trade name) Medicinal form, dosage Diplacine dichloride Sol. for inj. 2% Pipecuronium bromide Pwd. for inj. 0.004 Suxamethonium iodide Sol. for inj. 2% Tubocurarine chloride Sol. for inj. 1%

Glossary Apnoea is the absence of respiratory movements. Cachexia is the emaciation of the organism. Polarization (the state of rest) → depolarization (transmission of a nervous impulse) → repolarization (return to the state of rest) are the obligatory sequential states of the postsynaptic membrane. Reposition is matching of the bone fragments. Controlled respiration is the artificial respiration with the help of the specific equipment.

ADRENERGIC MEDICINES (ADRENOMIMETICS, ADRENERGIC AGONISTS) In the adrenergic synapses the noradrenaline (NA) neurotransmitter and the hormone adrenaline are functioning. The main one is NA. NA, adrenaline and dophamine are catecholamines, as they have oxygroups at the 3rd and 4th position of the aromatic ring. The inactivation of NA and

30 adrenaline is performed by two enzymes: catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO). These two catecholamines interact with different receptors: 1, 2, 1, 2, 3 –AR. Table 2 Distribution in organs and effects of the adrenoreceptors in case of stimulation

Location Functions

-adrenoreceptors 1 and 2-adrenoreceptors Vessels (the number Skin and mucous Skeletal muscles > heart > of receptors) membranes > kidneys > lungs > brain > abdominal abdominal cavity organs cavity organs > skeletal muscles > lungs > brain Dilation (2) Constriction Heart: rate and Increase ( ) -- 1 contractility

Bronchial tone -- Decrease (2) Uterus Contraction Relaxation (2)

There are two subtypes of 1-AR located on the postsynaptic membrane: 1A and 1B-AR. 1A-AR are located in the smooth muscles of the gland, the urinary bladder’s cervix and the prostatic part of the urethra. When stimulating them the tone of the smooth muscles of the organs mentioned increases. 1B-AR are located in the smooth muscles of the vascular wall. When stimulating them the tone of vessels increases. 2-AR are located on the presynaptic membrane and outside synapses: in the vasomotor centre and on thrombocytes. The stimulation of 2-AR causes aggregation of thrombocytes (and β2-AR, visa versa, decrease it). The physiological role of the presynaptic α2-AR is also in their participation in the system of the negative feedback that regulates the release of noradrenaline and the vascular tone. Thus, when stimulating α2-AR the release of noradrenaline into a synapse and the excitability of the vasomotor centre decrease. It leads to the BP decrease. The stimulatory effects of catecholamines are mainly connected with the activation of 1- AR (table 2), whereas the inhibitory effects (excluding the heart) occur with activation of β-AR. Noradrenaline activates mainly α1-AR and adrenaline activates all types of AR (but stronger β-AR). At present β3-AR are also discovered, they together with β2-AR when stimulated increase the processes of glycogenolysis and lipolysis.

Classification of medicines α1- adrenomimetics, β1- adrenomimetics *, α1, α2, β1, β2- α2- adrenomimetics* β2- adrenomimetics, adrenomimetics β1+β2- adrenomimetics ** Norepinephrine Dobutamine Epinephrine

31 Phenylephrine Fenoterol Ephedrine hydrochloride hydrochloride Salbutamol Xylomethazoline Isoprenaline ** Oxymethazoline Orciprenaline sulphate ** Tetrizoline *

The mechanism of action Medicines of this group stimulate AR: - α1- adrenomimetics stimulate α1-AR of vessels; - α2- adrenomimetics stimulate α2-AR of the vasomotor centre and sympathetic nerve fibres; - β1-adrenomimetics stimulate β1-AR of the myocardium; - β2-adrenomimetics stimulate β2-AR of the bronchi, uterus and vessels; - β1+β2-adrenomimetics stimulate β1- and β2-AR of the myocardium, bronchi, uterus, vessels; - α1, α2, β1, β2- adrenomimetics stimulate α1-, α2-, β1-, β2-AR. Ephedrine hydrochloride is an indirect-acting adrenomimetic (sympathomimetic) that suppresses the activity of MAO and COMT and the recapture (re-uptake) of catecholamines and it leads to the increase of the neurotransmitter’s concentration in the synaptic cleft.

Pharmacodynamics (effects) → Indications Stimulation of α1-AR: the vasoconstrictive Shock, collapse, hypotension, effect, the BP increase. ―Centralization of the conjunctivitis, prolongation of the blood circulation‖ – the of local anesthetics effect the skin, subcutaneous tissue, mucous membranes, organs of the abdominal cavity (α1-AR), but (because of the stimulation of β2- AR) dilation of vessels (improvement of the blood circulation) of heart, brain, lungs, skeletal muscles Stimulation of α2-AR: the hypotensive effect Essential hypertension (EH), hypertensive crisis Stimulation of β1-AR: the cardio-stimulating Heart stoppage, cardiogenic shock, effect (the positive inotropic and chronotropic bradyarrhythmia effects), the increase of the oxygen consumption by myocardium Stimulation of β2-AR: the broncholytic effect BA, chronic asthmatic bronchitis Stimulation of β2-AR: the tocolytic effect Threatened preterm labour (decrease of the uterine tone and contractions Stimulation of β2- and β3-AR: the Hypoglycemic coma enhancement of glycogenolysis and lipolysis Side effects → Contraindications Tachycardia, hyperglycemia, Coronarosclerosis, mellitus, EH hypertension (excluding Clonidine) (excluding Clonidine)

32 Adrenomimetics reproduce in organs the same effects, which are observed when irritating the postganglionic sympathetic nerves. The effects of adrenomimetics on the cardiovascular system and the bronchial tone are the most practically useful.

The pharmacological “face” of adrenergic agonists Medicines Adrenoreceptors Duration α1 α2 β1 β2 of action Epinephrine +++ - ++++ +++ + Ephedrine + - +++ ++ +++ Norepinephrine ++++ - + + + Tetrizoline +++ - - - ++ Clonidine - +++ - - ++

Dobutamine - - +++ - + Salbutamol - - - +++ +++ Salmeterol - - - ++++ +++++ Terbutaline - - + +++ ++++ Orciprenaline - - + +++ ++++ Isoprenaline - - ++ +++ ++ The list of medicines INN, (Trade name) Medicinal form, dosage Clonidine (Clofelin) Sol. for inj. 0.1%; tabl. 0.00075 Dobutamine (Dobutrex) Sol. for inj. 0.5% Ephedrine hydrochloride Sol. for inj. 5%; tabl. 0.01 Epinephrine (Adrenaline hydrochloride, Adrena- Sol. for inj.0.1% line hydrotartrate) Fenoterol (Berotek) Sol. 0.1% Isoprenaline (Isadrine, Novodrine) Sol. for inj. 1%; tabl. 0.005 Norepinephrine (Noradrenaline) Sol. for inj. 0.2% Oxymethazoline Sol. 0.05% Orciprenaline sulphate (Alupent, Asthmopent) Sol. for inj. 0.1%; tabl. 0.02 Phenylephrine hydrochloride (Mesaton) Sol. for inj.1% Salbutamol Sol. for inj. 0.1%; tabl. 0.002 Tetrizoline (Visin, Tizin) Sol. 0.01; 0.05% Xylomethazoline (Galazoline) Sol. 0.1%

Glossary Hypoglycemic coma is an acute decrease of the level in blood. The increase of glycogenolysis and lipolysis is the increase of disintegration of carbohydrates and lipids that leads to the increase of the glucose and lipid level in blood.

ANTI-ADRENERGIC MEDICINES (ADRENOBLOCKERS AND SYMPATHOLYTICS) According to the presence of two types of AR anti-adrenergic medicines (adrenergic antagonists) of this group are divided into α- and β-adrenoblockers

33 (adrenolytics) with different pharmacodynamics and the spectrum of application. Sympatholytics are non-selective anti-adrenergic medicines.

Anti-adrenergic medicines

Adrenoblockers (direct) Sympatholytics (indirect)

α β α+β (hybrid)

α1- α1 α1+α2 β1 β1+β2

α α 1A 1B

Fig. 2. The classification of anti-adrenergic medicines.

α-Adrenoblockers

Classification of medicines α1-, α2*-adrenoblockers α1+α2- adrenoblockers Tamsulosine Yohimbine* Proroxan Phentolamine Doxazosine Prazosine Nicergoline

The mechanism of action α-Adrenoblockers possess a competitive mechanism of blocking effect, though their structural similarity to catecholamines is slightly marked. Medicines of this group block both the postsynaptic α1-AR and the presynaptic α2-AR.

Pharmacodynamics (effects) → Indications Blockade of the α1B-AR in vessels decreases the EH, endarteritis, sympathetic influence on vessels. As a result the bedsores, vasodilating and hypotensive effects occur pheochromocytoma Blockade of α1A-AR decreases the tone of the smooth Benign hyperplasia of muscles of the urethra prostatic part and the urinary the prostate (BHP) bladder cervix (adenoma) Blockade of α2-AR improves the blood supply of small Psychogenic impotency, pelvis organs and increases male climacterium Side effects → Contraindications Orthostatic collapse, hypotension Hypotension, sclerosis of the coronary and brain vessels

The pharmacological “face” of α-adrenoblockers Medicines ↓ Duration of Peculiarities of using/ BP action, h pharmacodynamics Phentolamine ++ 6 Pheochromocytoma, but not EH; insulin level ↑ Proroxan ++ 6 Sedative, , effects; for motion sickness

34 Dihydroergotamine ± 6 Migraine Nicergoline + 6 Spasmolytic effect; migraine, dis- orders of the cerebral blood circulation Prazosine ++ 8 Adenoma, ↑ the sensitivity to insulin Doxazosine ++ 24 Causes the ―phenomenon of the first dose‖ (collapse), the hypolipidemic effect Tamsulosine ± 20 Adenoma (block of α1A-AR) Yohimbine Impotency

β-Adrenoblockers Classification of medicines β1-adrenoblockers β1+β2-adrenoblockers Metoprolol Betaxolol Talinolol Oxprenolol Bisoprolol Atenolol By the duration of the effect the medicines can be divided into short acting (Propranolol, Metoprolol, Oxprenolol), middle-acting (Pindolol) and long-acting (Sotalol, Atenolol) ones.

The mechanism of action Medicines block β-AR of the heart, bronchi, vessels and other organs. They are similar to Isoprenaline in their chemical structure. β1-Adrenoblockers are called cardioselective, β1+β2- adrenoblockers are called non-cardioselective ones. Pharmacodynamics (effects) → Indications The β1-AR blockade in the myocardium: the effect– Ischemic decrease of the heart rate and contractility resulting in the decrease of heart oxygen consumption by myocardium disease (angina pectoris) The β1-AR blockade of the heart’s conductive system – the Tachyar- antiarrhythmic effect rhythmia The β1-AR blockade of the heart (decrease of the heart function) and Hypertensio kidneys (the renin-angiotensin system activity decrease) – the n hypotensive (antihypertensive) effect Side effects → Contraindications Bradycardia, bronchospasm, angiospasm, Bradycardia, BA, peripheral blood hypotension circulation disorders, hypotension The β2-AR blockade causes the constriction (including the coronary vessels), increase of the bronchial tone and uterine contractions, suppression of glycogenolysis and decrease of the glucose level in blood.

The pharmacological “face” of β-adrenoblockers Medicines ↓ BP, h MS ISM Peculiarities Metoprolol 6-8 - - Prophylaxis of migraine Betaxolol 12-24 + - Glaucoma

35 Talinolol 24 - - Does not cause the orthostatic collapse Atenolol 24 - - Does not penetrate through the BBB Propranolol 6-8 + - Does not cause the orthostatic collapse Oxprenolol 6-8 + + Side effects are less than in propranolol Sotalol 24 - - The marked anti-arrhythmic effect MS is the membrane stabilizing effect, ISM is the inner sympathomimetic (less side effects) activity.

β1- adrenoblockers are safer than β1+ β2-adrenoblockers, as they practically do not cause bronchospasm connected to the β2-AR blockade. However, when taking β1-adrenoblockers for a long period of time, the tolerance to these medicines develops and it often leads to the dose increase and the loss of selectivity.

Sympatholytics (indirect-acting anti-adrenergic medicines)

Reserpine and Octadine belong to this group.

The mechanism of action These medicines turn off the sympathetic innervation selectively: decrease the synthesis and release of a neurotransmitter, exhaust the noradrenaline reserve in the presynaptic membrane.

Pharmacodynamics → Indications Hypotensive effect EH Side effects → Contraindications Enhancement of the parasympathetic innervation Peptic ulcer, BA (hypersecretion in the GIT, bronchospasm)

The pharmacological “face” of sympatholytics Medicines Max ↓ BP at Peculiarities Reserpine 8-10 day A weak neuroleptic and sedative effects; it is used in the initial stage of EH Octadine 7-8 day Does not penetrate through the BBB, cause the orthostatic collapse; it is used in the severe form of EH

The list of medicines INN, (Trade name) Medicinal form, dosage Atenolol Tabl. 0.01 Betaxolol (Locren) Tabl. 0.001; sol. 0.5% Bisoprolol (Concor) Tabl. 0.005 Dihydroergotamine Tabl. 0.025; sol. for inj. 1% Doxazosine (Cardura) Tabl. 0.002 Metoprolol (Vasocardine) Tabl. 0.05; sol. for inj. 0.1%

36 Nicergoline Tabl. 0.005 Oxprenolol Tabl. 0.02 Octadine Tabl. 0.025 Phentolamine Tabl. 0.025 Proroxan (Pyrroxan) Tabl. 0.15; sol. for inj. 1% Prazosine (Adversuten) Tabl. 0.005 Propranolol (Anaprilin) Tabl. 0.01; sol. for inj. 2.5% Reserpine Tabl. 0.0001 Sotalol Tabl. 0.08; sol. for inj. 0.1% Talinolol (Cordanum) Tabl. 0.05; sol. for inj. 0.2% Tamsulozine (Omnic) Caps. 0.0004 Yohimbine hydrochloride Tabl. 0.005

Glossary BHP is a benign hyperplasia (tumour) of the prostate (adenoma). IHD is the ischemic or coronary heart disease (stenocardia or angina pectoris and myocardial infarction). Pheochromocytoma is a benign tumour of the adrenal medulla that causes a marked increase of adrenaline secretion and, therefore, the BP increase.

III. PAIN PHARMACOCORRECTORS

Local anesthetics (see above), general anesthetics and analgesics belong to this group of medicines.

GENERAL ANESTHETICS Narcosis (in Greek narkosis means ―numbness‖) is a state when consciousness and all types of sensitivity are absent, skeletal muscles are relaxed, reflexes are suppressed. The state of narcosis (or general anesthesia) (indication of anesthetics) consists of 4 successive stages (pharmacodynamics of medicines): analgesia (short-term period) - the loss of pain sensitivity; stimulation (operations are not performed) – decrease of inhibitory processes, fluctuation of blood pressure, heart rate, breathing frequency; surgical narcosis - all types of sensitivity and consciousness are absent, the complete myorelaxation; awakening - returning of all organism’s functions in a reverse order.

Classification of medicines Medicines for inhalation narcosis Medicines for non-inhalation narcosis Ftorotan Propanidide Enfluran Ether for narcosis Sodium oxybutyrate

The mechanism of action Lipoid, protein, synaptic and other theories of action for anesthetics have been suggested. The following changes caused by these medicines are distinguished while their acting: disorders of the ions transport through the membranes of neurons, activation of the endogenous antinociceptive and GABA-ergic systems, inhibition of cholin-, dophamin- and serotoninergic processes in the CNS.

37 The pharmacological “face” of general anesthetics Medicines Acti- Going out Myo- Stimula- Narcosis Other effects vity from rela- tion stage ma- narcosis* xation naging Ftorotan +++ ++ ++  +++  of BP, breathing; + bradycardia Enfluran +++ +++ +++ + ++  of BP, breathing Nitric + ++++ - +++ +++ A component of the oxide combined narcosis Ether for ++ + ++ +++ ++  of BP, irritates mucous narcosis membranes Propani- +++ ++ ++ - - Laryngospasm, thrombo- dide + sis, irritation. A short- term narcosis Thiopental +++ +++ +++ - - Convulsions, + laryngospasm Sodium + ++  - Sedative, hypnotic, anti- oxy- hypoxic effects butyrate Ketamine + +++ - - - BP, hallucinations, convulsions * - the speed of going out from narcosis (awakening).

The list of medicines INN, (Trade name) Medicinal form, dosage Enfluran Vial 250 ml Ether for narcosis Vial 140 ml Ftorotan Vial 250 ml Ketamine Sol. for inj. 5% Nitric oxide Balloon metal. Propanidide (Sombrevin) Sol. for inj. 5% Sodium oxybutyrate Sol. for inj. 20% Sodium thiopental Vial 1.0

Glossary Antinociceptive system is the endogenous system of analgesia.

ANALGESICS

Analgesics (in Greek an means ―negation‖ and algos is ―ache‖) are medicines that suppress selectively the pain sensitivity. Depending on their chemical structure, the mechanism of action and pharmacodynamics peculiarities they are divided into narcotic (big) and non-narcotic (small) analgesics.

Narcotic analgesics

Pain and analgesia are provided by two functional systems – the nociceptive system (in Latin noceo is ―I damage‖) that perceives pain and take part in its

38 transmission, and antinociceptive one that suppresses pain. The initial nociceptive structures are nociceptors – receptors, which perceive the pain stimulation. They are located in the skin, muscles, mucous membranes, arteries, capsules of and internal organs. A pain impulse is transmitted to the central neurons along afferent nerves with the help of the pain mediators. receptors (OR) and their endogenous ligands (ligo is ―I connect‖) also participate in the pain perception and analgesia. OR are located in the presynaptic membranes of neurons, which take part in the transmission of nociceptive impulses both in the CNS and tissues. They are the sites of membranes with a high sensitivity towards their ligands (endo- and exogenous) and perform the inhibitory (antinociceptive) function. Endogenous ligands of OR are analgesic neuropeptides: encephalins and endorphins. They bind to OR and as a result, the output of algogens – the pain mediators (acetylcholine, , prostaglandins, catecholamines, serotonin, histamine), which take part in transmission of nociceptive impulses into the synaptic cleft, is delayed. There are 5 types of OR: μ (myu), χ (cappa), ζ (sigma), δ (delta), ε (epsilon). The role of μ-receptors is particularly important as they provide analgesia, the sedative effect, inhibition of the respiratory centre, bradycardia, myosis, decrease of the GIT motility, euphoria and drug addiction. Narcotic analgesics, or (OA), inhibit or decrease pain, in high doses they cause sleep and if they are used recurrently, physical and psychological dependence – drug addiction – develop.

Classification of medicines Natural and semi- Synthetic synthetic* Agonists of receptors Agonists-antagonists and antagonists* of opioid receptors Suphentanyl Omnopone Phentanyl * Pyritramide hydrochloride*

The mechanism of action The mechanism of the analgesic effect of opioids is stipulated by their action on OR and the activation of the endogenous antinociceptive system. As the result of presynaptic OR stimulation the release of algogens decreases, and it leads to disorder of the pain impulses transmission.

Pharmacodynamics (effects) → Indications Strong and very strong pain caused by traumas (excluding the craniocerebral trauma, hemorrhagic stroke), myocardial infarction, massive burns, shock, malignant Analgesic tumours, acute inflammatory processes (peritonitis, cholecystitis), colics; caused by the excessive pain; prevention of the traumatic shock;

39 Antitussive (anti- Cough in pneumothorax, lung ; operations on the cough) thoracal organs; persistent dry cough Anti-emetic Strong uncontrolled vomiting of the central genesis, which cannot be stopped by other medicines (in radiation sickness, etc.) Inhibition of the respi- Acute (small doses of morphine cause ratory centre the rate decrease and the depth increase of breath movements and it leads to the breath relief) Stimulation of the Radiography of the GIT vagus nerve (parasym- pathetic innervation prevails: the increase of the smooth muscles tone, etc.) Stimulation of the Diagnostic importance when intoxicated by morphine and oculomotor nerve other opioids (myosis) Side effects → Contraindications Drug dependence Chronic pain (excluding cancer diseases) (physical, psychological), addiction, abstinence Inhibition of the Pregnancy, labour, lactation, craniocerebral trauma, respiratory centre hemorrhagic stroke, children under 2 years old, patients over 60 years old

The pharmacological “face” of narcotic analgesics Medicines Analgesia Duration of Inhibition of Addiction action breathing Morphine (M) A reference-drug 6 ++ ++ Phentanyl 200 times > M 0.5 ++ ++ Buprenorphine 20-30 times > M 9   Butorphanol 3-5 times > M 9 +  Pyritramide 2 times > M 9  + Trimeperidine < M 4 + + Codeine < M 6 +  Pentazocine < M 5   Tramadol < M 9 - 

The list of medicines INN, (Trade name) Medicinal form, dosage Buprenorphine (Bupremen) Sol. for inj. 0.03%; tabl. 0.0002 Butorphanol (Moradol) Sol. for inj. 0.2% Codeine (Codeine phosphate) Tabl. 0.015 Ethylmorphine hydrochloride (Dionine) Tabl. 0.015

40 Morphine Sol. for inj. 1%; tabl. 0.01 Naloxone Sol. for inj. 0.04% Omnopone Sol. for inj. 1; 2% Pentazocine Sol. for inj. 1; 2% Phentanyl Sol. for inj. 0.005% Pyritramide (Dipidolor) Sol. for inj. 0.75% Suphentanyl (Suphentane) Sol. for inj. 0.0005% Tramadol (Tramal) Sol. for inj. 5%; caps. 0.05 Trimeperidine (Promedol) Sol. for inj. 1; 2%; tabl. 0.025

Glossary Analgesia is the pain relief. Drug dependence, drug addiction, is a strong desire for regular taking a medicine with a stable psychological and on it and with the development of abstinence after stopping taking it. Myosis is constriction of pupil. Premedication is the medicinal preparation for narcosis for increase of its effectiveness and decrease of the dose of anesthetics. Habituation (tolerance) is the decrease of the therapeutic effect after repeated administration of a medicine. Euphoria is the state of the imaginary psychological well-being, causeless mood improvement, withdrawal from reality; it is the basis of the psychological dependence to psychotropic medicines.

Non-narcotic analgesics (Analgesics-antipyretics) Non-narcotic analgesics (NNA) are medicines with a moderate analgesic effect. They are different from OA by the absence of the development of addiction or habituation, as well as the presence of antipyretic and anti-inflammatory (weak) effect. Non-steroidal anti-inflammatory drugs (NSAIDs) are close to NNA by their mechanism of action, their difference is in the intensity of anti-inflammatory effect.

Classification of medicines With the central Peripheral-acting Spasmoanalgesics component of (monomedicines* and action combined ones) Nephopam Sodium methamizole* Baralgetas Pentalgin Spasmalgon Citramone Sedalgin Tempalgin

The mechanism of action NNA block cyclooxygenase (COG) enzyme, which leads to the inhibition of the prostaglandins (PGs) synthesis in the site of inflammation and the CNS, the decrease of nociceptors’ sensibilization to the action of algogens and the disorder of the pain impulses transmission along the afferent nerves. NNA decrease the mechanical compression of nociceptors due to the anti-edemic effect of medicines. The pyrogenic effect of PGs towards the thermoregulation centre also decreases, the

41 heat emission increases due to the dilation of the skin vessels and increase of sudation and the heat production decreases in the same time.

Pharmacodynamics (effects) → Indications Analgesic Acute and chronic pains, which are not dangerous to life (toothache, headache, pain in joints, muscular pain, etc.), neuralgia Antipyretic Fever, ARVI, flu Side effects → Contraindications Dyspepsia, ulcerogenic effect GIT diseases (gastritis, peptic ulcer) Inhibition of hemopoiesis, Diseases of the blood (agranulocytosis, formation of methemoglobin methemoglobinemia) Nephro- and hepatotoxic effects Marked renal and liver dysfunctions

The pharmacological “face” of non-narcotic analgesics Medicines Analgesic Antipyre- Anti-inflam- Other effect tic effect matory effect peculiarities/effects Sodium ++ +  methamizole (reference) Paracetamol + ++ A narrow interval of the therapeutic action Ketorolac +++  Tempalgin +++ Tranquilizing Baralgetas +++ Spasmolytic Spasmalgon ++  Spasmolytic Sedalgin +++ It contains ASA, Pentalgin , Codeine, Citramone +++  It contains ASA, Caffeine, Paracetamol

The list of medicines INN, (Trade name) Medicinal form, dosage Baralgetas Tabl.; supp.; sol. for inj. 5 ml Ketorolac (Ketanov) Tabl. 0.075 Nephopam Tabl. 0.03; sol. for inj. 2% Paracetamol (Panadol) Tabl. 0.5 Pentalgin, Sedalgin, Spasmalgon, Tabl. Tempalgin, Citramone Sodium methamizole (Analgin) Tabl. 0.5; sol. for inj. 50%

Glossary Afferent nerves (sensitive) are peripheral nerves that transmit an impulse from afferent receptors to the CNS. Dyspepsia is , vomiting, diarrhea. Antipyretic effect is the decrease of the body temperature in fever. Pyrogenic effect is the ability of pyrogens to increase the body temperature. Prostaglandins are biologically active

42 substances that play a role of mediators and modulators of inflammation, pain, fever. Ulcerogenic effect is the ability to cause ulceration of the GIT.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines that possess anti-inflammatory, analgesic and antipyretic effects. The synthesis of prostaglandins activates in the site of inflammation under the action of different damaging factors. It is carried out involving the following cyclooxygenase enzymes: cyclooxygenase-1 (COG1) and cyclooxygenase-2 (COG2). COG1 is constitutional, it performs such physiologic functions as: participation in the synthesis of PGs, stabilizing the cellular membrane with the cytoprotective effect in the GIT and kidneys and regulation of the thrombocytes function. COG2 is ―inflammatory‖, which controls the synthesis of PGs during inflammatory processes. PGs are mediators and modulators of inflammation, they activate the production of other mediators of inflammation (histamine, kinins, serotonin, complement, lysomal enzymes, etc.) and participate in developing the pain syndrome and fever. Under the action of PGs and other mediators of inflammation vessels dilate, the permeability of the vascular wall increases, the blood plasma goes into the interstitial area, edema develops, hyperemia appears, nociceptors are sensitized (their sensitivity to algogens increases).

Classification of medicines Derivatives of phenylpropionic and and phenylacetic* acids indolacetic acid* Acetylsalicylic acid (ASA) Phenylbutazone Lysin acetylsalicylate Ibuprophen Indomethacin* Sodium * Oxycams Coxibs Combined and other* medicines Meloxycam Reopyrine Sigan Pyroxycam *

The mechanism of action According to the mechanism of action NSAIDs are divided into selective COG1 inhibitors (ASA in small doses); non-selective COG1 and COG2 inhibitors (ASA, Sodium diclofenac, Indomethacin, Phenylbutazone, etc.); selective COG2 inhibitors (Meloxycam, Nimesulide); highly selective COG2 inhibitors (Celecoxib, Rofecoxib). The most important chain in the mechanism of action of NSAIDs is the ability to inhibit COG (COG1, COG2 or COG1+COG2). The decrease of the COG activity decreases the synthesis of PGs and other inflammatory mediators. NSAIDs also decrease the energy supply in the site of inflammation, inhibit subcortical pain centres, decrease the pyrogenic effect of PGs on the thermoregulation centre, increase the heat emission and decrease the aggregation of thrombocytes.

43 Pharmacodynamics (effects) → Indications Anti-inflammatory Inflammatory diseases of the connective tissue (collagenoses): rheumatism, systemic lupus erythematosus, etc.; arthrites, arthroses, osteochondrosis, radiculitis Analgesic Acute and chronic pain: headache, pain in joints, muscular pain (myalgia), toothache, algomenorrhea, neuralgia, injuries of ligaments, bruises, etc. Antipyretic ARVI, hyperthermia (fever) Anti-aggregant Hypercoagulation syndrome, prophylaxis of postoperative thrombosis, trombophlebitis, disorder of the cerebral blood circulation, IHD, atherosclerosis Side effects → Contraindications Ulcerogenic effect, dyspepsia Peptic ulcer, gastritis Allergic reactions BA, allergic bronchitis, etc. Bleedings Bleedings, thrombocytopenia, hemophilia

The pharmacological “face” of NSAIDs

Anti-inflammatory effect Diclofenac > Pyroxycam ≥ Indomethacin > Meloxycam > Ketoprofen > Phenylbutazone = Ibuprophen > Acetylsalicylic acid.

Analgesic effect Diclofenac > Indomethacin > Pyroxycam > Ibuprophen > Ketoprofen ≥ Acetylsalicylic acid ≥ Phenylbutazone.

Antipyretic effect Diclofenac > Pyroxycam > Indomethacin > Ibuprophen > Acetylsalicylic acid = Phenylbutazone.

Ulcerogenic effect Indomethacin = Acetylsalicylic acid > Pyroxycam > Phenylbutazone > Diclofenac = Ibuprophen.

The list of medicines INN, (Trade name) Medicinal form, dosage Acetylsalicylic acid () Tabl. 0.5 Celecoxib Caps. 0.2 Ibuprophen (Brufen) Tabl. 0.2 Indomethacin (Methindol) Tabl. 0.05 Ketoprofen (Ketonal) Tabl. 0.2 Lysin acetylsalicylate (Acelysin, Laspal) Pwd. for inj. 2.0 Meloxycam (Movalis) Tabl. 0.015 Nimesulide (Mesulide, Nimulide, Nimesil) Tabl. 0.2 Phenylbutazone (Butadione) Tabl. 0.05 Pyroxycam (Oxycam) Caps. 0.2 Reopyrine Sol. for inj. 5ml Rofecoxib Tabl. 0.025

44 Sigan Tabl. № 4 Sodium diclofenac (Voltaren, Orthophen) Tabl. 0.025

Glossary Antiaggregant effect is decrease of aggregation (adhesion) of thrombocytes. Arthritis is the inflammatory disease of a . Arthrosis is the disease of joints with degeneration of articular cartilage and deformation of articular surfaces. Algomenorrhea is painful menstruation. Hemophilia is inherited decrease of the blood coagulability. Collagenoses are systemic autoimmune diseases with a diffuse damage of the connective tissue. Osteochondrosis is the disease that characterizes by a dystrophic process in the bone and cartilaginous tissue. Radiculitis is the inflammation of some radicles of the spinal nerves. Rheumatism is the inflammatory infectious allergic disease that damages the cardiovascular system, joints and the nervous system. Systemic lupus erythematosus is the chronic systemic inflammatory autoimmune disease of the connective tissue and vessels. Thrombophlebitis is inflammation of veins with their simultaneous thrombosis.

IV. MEDICINES SUPPRESSING THE CENTRAL NERVOUS SYSTEM (CNS )

Neuroleptics, tranquilizers, sedative, hypnotic, , antiparkinsonic medicines belong to this group.

NEUROLEPTICS ( MEDICINES, MAJOR TRANQUILIZERS)

Neuroleptics are psychotropic medicines that are able to reveal the inhibitory action on the CNS (without consciousness disturbing): eliminate hallucinations, delirium and stop the psychomotor excitation (motor and speech).

Classification of medicines Derivatives of butyro- , phenone dibenzodiazepine*, ** Chlorprothixene Sulpyrid** Perphenazine hydrochloride Closapine* Derivatives of phenothiazine, butyrophenone and thioxanthene are called ―typical‖ neuroleptics as they lead to development of drug-induced parkinsonism. The rest of neuroleptics cause such complications rather seldom, and that is why they are called ―atypical‖ (closapine, sulpyrid).

The mechanism of action The mechanism of action of neuroleptics is complex as they disturb the functions of many neurotransmitters in the CNS blocking different receptors (dophamine, α-AR, M-ChR-, H1-histamine receptors and serotonin-5HT2-receptors).

45 The antipsychotic effect is bound to blocking of the central dophamine D2- receptors located mainly in the reticular formation (the activating influence on the brain cortex is eliminated), in the nuclei of midbrain, the limbic system and the hypothalamus. Not only the antipsychotic effects of neuroleptics bound to inhibition of the mediator activity of dophamine, but also their main side effect – extrapyramidal disorders, which are similar with the Parkinson`s disease symptoms. A highly selective binding to D4-receptors is characteristic for ―atypical‖ neuroleptics. The neuroleptic effect is stipulated by blockade of the central α- adrenoreceptors in the ascending part of the reticular formation, the limbic system and the hypothalamus. The potentiating effect of neuroleptics is caused by blockade of α- adrenoreceptors of the brain’s reticular formation. The anti-emetic effect is caused by blockade of dophamine (D2) and serotonin receptors of the medullar ―trigger-zone‖ and halt of signals transmission into the emetic centre. The hypothermic effect is the result of adreno- and serotonin receptors blockade and, therefore, decrease of the activity of the hypothalamic thermoregulation centres (decrease of the heat production and increase of the heat emission). The antihistaminic effect is caused by H1-histamine receptors blockade. The hypotensive effect is the result of α-adrenoreceptors blockade in the hypothalamus and peripheral vessels.

Pharmacodynamics (effects) → Indications Antipsychotic, neuroleptic Psychosis Potentiating (for medicines that Neuroleptanalgesia, potentiation of suppress the CNS) narcosis Anti-emetic Uncontrolled vomiting of the central genesis Hypothermic Controlled hypothermia during narcosis Antihistaminic Severe itching neurodermatitis Hypotensive Severe forms of hypertension Side effects → Contraindications Neuroleptic syndrome, drug-induced parkinsonism, Depression, dyspepsia parkinsonism

The pharmacological “face” of neuroleptics

Antipsychotic effect: Haloperidol > Droperidol > Closapine > Chlorprothixene = Chlorpromazine = Perphenazine hydrochloride = Sulpyrid > Levomepromazine.

Neuroleptic effect: Derivatives of phenothiazine = butyrophenone > thioxanthene > Closapine > Sulpyrid.

46 Potentiating effect: Haloperidol > Droperidol > Levomepromazine > Chlorpromazine.

Anti-emetic effect: Haloperidol > Perphenazine hydrochloride > Droperidol > Sulpyrid > Chlorpromazine.

Sedative effect: Chlorpromazine = Levomepromazine = Closapine > Chlorprothixene > Perphenazine hydrochloride = Haloperidol = Droperidol > Sulpyrid.

The list of medicines INN, (Trade name) Medicinal form, dosage Chlorpromazine (Aminazine) Sol. for inj. 2.5%; dr. 0.025 Chlorprothixene (Cloxane) Tabl. 0.05 Closapine (Azaleptine) Tabl. 0.025 Droperidol Sol. for inj. 0.25% Haloperidol Tabl. 0.5; sol. for inj. 0.5% Levomepromazine (Tisercine) Tabl. 0.025 Perphenazine hydrochloride (Etaperazine) Tabl. 0.01 Sulpyrid (Eglonyl) Tabl. 0.2

Glossary The antipsychotic effect is elimination of delirium and hallucinations. The hypothermic effect is decrease of the body temperature bellow the norm. Neuroleptanalgesia is a peculiar form of narcosis (with the partial presence of consciousness) that is reached by the combination of neuroleptics and narcotic analgesics that leads to potentiation of their action. The neuroleptic syndrome is hyperthermia with the extrapyramidal and autonomic nervous system disorders that can lead to death. The neuroleptic effect is the ―will paralysis‖ appearing as the result of the inhibition of the psychomotor excitation (motor and speech) and patient’s initiative. Psychoses are severe diseases of CNS, their main symptoms are delirium and hallucinations.

TRANQUILIZERS (MINOR TRANQUILIZERS, , ATARACTICS, ANTIPHOBIC MEDICINES)

Tranquilizers (in Latin tranquillare is ―to make calm‖) are medicines that remove selectively fair, anxiety, emotional tension increased restlessness and are used mainly in neuroses and the related states. Classification of medicines Derivatives of Derivatives of other chemical groups Hydroxysine Trimetosine

The mechanism of action They decrease the excitability of subcortical regions of the brain (the limbic system, the thalamus, the reticular formation, the hypothalamus) that are responsible

47 for emotional reactions, inhibit the interaction between these structures and the brain cortex. stimulate mainly benzodiazepine receptors and that leads to activation of GABA-receptors and intensification of the inhibitory functions of GABA. Pharmacodynamics (effects) → Indications Neuroses, mild psychoses Hypnotic Insomnia (especially caused by negative emotions) Sedative Neurogenic diseases Anticonvulsant Convulsions (epilepsy) Potentiating Premedication Side effects → Contraindications Drowsiness, weakness, disorders of Activities that require rapid psychomotor attention and locomotion, tolerance, reactions, long-term courses of treatment, addiction increase of doses Medazepam, Gidazepam, Trimetosine are ―day time‖ tranquilizers as they cause less inhibition of CNS than other medicines, therefore, they can be used in day time. The pharmacological “face” of tranquilizers Tranquili- Addiction / Medicines SE Other effects zing effect tolerance Diazepam +++ +/+ ++ Anticonvulsant, hypnotic, Chlordiaze- ++ +/+ + sedative, spasmolytic poxide (diazepam), vegetostabilizing, myorelaxant, potentiating (diazepam, chlordiazepoxide) Lorazepam +++ +/+* + Accumulation, anticonvulsant, hypnotic Alprazolam +++ + Anticonvulsant, Gidazepam ++  Anticonvulsant, potentiating, stimulating Hydroxysine + + Analgesic, myorelaxant, anti- emetic SE – side effect; * – in the long-term administration

The list of medicines INN, (Trade name) Medicinal form, dosage Alprazolam (Xanax) Tabl. 0.001 Chlordiazepoxide (Chlozepide, Elenium) Tabl. 0.01 Diazepam (Relanium, Sibazone) Tabl. 0.005; sol. for inj. 0.5% Gidazepam Tabl. 0.05 Hydroxysine (Atarax) Tabl. 0.01 Lorazepam (Merlit) Tabl. 0.001 Medazepam (Mezapam, Rudotel) Tabl. 0.01 Trimetosine (Trioxasine) Tabl. 0.3

48 Glossary Anxiolytic (psychosedative, tranquilizing) effect is inhibition of the feeling of anxiety, fear, restlessness, uncertainty; decrease of psychic tension and emotional excitation. GABA is γ-aminobutyric acid, one of the main inhibitory mediators of the CNS. Neurosis is the disease of the CNS (curable) that is characterized by fear, anxiety, increased excitability and irritability. Neurogenic diseases are diseases provoked by the psychoemotional stress (peptic ulcer, hypertension, IHD). Premedication is the medicinal preparation of a patient to narcosis with the aim to increase its effectiveness and decrease the dose of general anesthetics.

SEDATIVE MEDICINES Sedative medicines (in Latin sedatio is ―calming‖) are medicines that cause a moderate sedative effect as a result of decrease of the CNS excitability and its reactivity to different stimuli. Classification of medicines Medicines of the plant origin Bromides* and combined medicines Persen extract * Corvalol Motherwort herb tincture Novo-passit Valocormide The mechanism of action They increase of the inhibitory processes in the CNS and decrease of the excitability of the reticular formation and the brain cortex.

Pharmacodynamics (effects) → Indications Sedative Mild form of neuroses, increased irritability, neurogenic diseases (hypertention, peptic ulcer, angina pectoris) Potentiating Intensification of effects of CNS depressants Side effects → Contraindications Decrease of the mental and physical Activities that require rapid psychomotor activity, feeling of fatigue, drowsiness reactions The peculiarity of sedative medicines is the low toxicity (lack of serious side effects); it allows using them widely in the ambulatory practice, especially while treating aged patients. However, if they are used for a long time, bromine-containing medicines cause bromism that is characterized by such symptoms as drowsiness, general inhibition, memory impairment, apathy, decrease of potency, lacrimation, cough, rhinitis, appearance of rash on the skin. The treatment of bromism is the following: stoppage of drug administration immediately; using of a great amount of sodium chloride (up to 20 g a day) and abundant drinking.

The pharmacological “face” of sedative medicines Effects Medicines Composition/other effects Sedative Spasmolytic Sodium +++ Anticonvulsant bromide Motherwort +  herb tincture

49 Medicines containing valerian: Valerian + + Spasmolytic extract Persen + + Mint, Melissa Corvalol ++ + Phenobarbital, mint oil Valocormide + + Sodium bromide, Convallaria, Belladonna, Menthol Novo-passit +++ + Guaphenesine, extracts of Crataegus, Humulus, Hypericum, Melissa, , Sambucus The list of medicines INN, (Trade name) Medicinal form, dosage Corvalol (Valocordin) Sol. 25 ml Motherwort herb tincture Tinct. 30 ml Novo-passit Sol.100ml Persen Tabl. Sodium bromide Sol. 3% Valerian extract (Valeran) Tabl. 0.02 Valocormide Sol. 30 ml Glossary Sedative effect is the soothing effect, decrease of excitability and irritability, conflictability, nervous tension.

HYPNOTIC MEDICINES Disorders of sleep (insomnia, somnipathies, hyposomnia) are one of the frequently met states appeared both independently (the primary insomnia) and in different somatic and psychic diseases (the secondary insomnia). There are three forms of insomnias that are stipulated by: 1) Disorder of the process of falling asleep (more than 40 min) (it is observed more frequently in young people with neurasthenia and overwork). 2) Frequent night awakening (more than 3 times a night). 3) Insufficient duration of a night sleep (less than 6 hours). Though the process of falling asleep is not disturbed a person wakes up in 2-5 hours and cannot fall sleep any more (―the sleep of an old man‖). If disorders of sleep are repeated more than 3 times a week, it should be corrected pharmacologically as insomnia (disorder of the physiological rhythm in work of the CNS) leads to overexcitation, fatigue, exhaustion of the brain, and therefore, to different forms of neurogenic disorders. Hypnotic medicines () are medicines that are able to restore the process of falling asleep, duration and depth of sleep if these processes are disturbed.

Classification of medicines Derivatives of Derivatives of cyclopyrrolone, Combined medicines benzodiazepine, *, barbituric acid* methylbutamide** Nitrozepam Reladorm

50 Phenobarbital* * ** (+diazepam)

The mechanism of action They inhibit polysynaptic regions in the brain; reduce the activating impulsation of the reticular formation on the brain cortex; intensify the function of a natural inhibitory mediator GABA. The drug interaction with benzodiazepine and barbituric receptors leading to increase of the GABA’s functions plays the main role in the mechanism of action of benzodiazepine and barbituric acid derivatives.

Pharmacodynamics (effects) → Indications Hypnotic Disorders of sleep Potentiating Intensification of the effects of CNS depressants Sedative (low doses) Mild neuroses, neurotic syndrome Side effects → Contraindications Apathy, drowsiness, Activities that require the rapid psychomotor reactions weakness

The pharmacological “face” of hypnotic medicines

Effective in Syndrome

disorder of

Medicines -

tolerance

After After

sleep

With

action

asleep

falling falling

drawal

sleep phases sleep

Dependence/

duration

Accumulation

Sleepduration Disorder of the Disorder Phenobarbital 8-10 + + +++ +++ +++ ++ ++/+ Cyclobarbital 4 + +++ ++ +++ + ++/+ 6-8 + + ++ ++ ++  +/+ Zolpidem 6 + + +  +/- Zopiclone 8 + +    Bromisoval 5-7 +  ++ + + +/+ Reladorm 8 + + + ++ +++ + ++/+ Besides the hypnotic effect, benzodiazepine derivatives have also the anticonvulsant, anxiolytic and myorelaxant effects, and derivatives of barbituric acid reveal the anticonvulsant effect. Most of hypnotic medicines cause disorders of the sleep structure, the syndromes of ―after (post-) action‖, ―return‖, ―withdrawal‖, physical and psychic dependence, tolerance, accumulation (especially barbiturates). At present one of the best hypnotic medicines, close to ideal, are Zopiclone and Zolpidem.

The list of medicines INN, (Trade name) Medicinal form, dosage Bromisoval (Bromural) Tabl. 0.3 Nitrazepam (Radedorm) Tabl. 0.01 Phenobarbital (Luminal) Tabl. 0.3; sol. for inj. 5% Reladorm (cyclobarbital+diazepam) Tabl.

51 Zolpidem (Ivadal) Tabl. 0.01 Zopiclone (Imovan) Tabl. 0.0075

Glossary Disorder of the sleep structure is the change of the ratio between phases of the fast sleep and slow-waved sleep. The syndrome of return is a torturing insomnia, nightmares, frequent waking up appearing after the administration of medicines, especially barbiturates, is stopped. The withdrawal syndrome is insomnia and discomfort developing as the result of the abrupt discontinuation of the drug administration, as a rule, on the background of the drug addiction formed. The syndrome of after action is the feeling of apathy, drowsiness after waking up.

ANTICONVULSANTS Anticonvulsant medicines decrease or stop convulsions in pathological states of the organism.

Classification of medicines Benzodiazepines Barbiturates Diazepam Valproic acid Phenobarbital Succinimides Iminostilbens Others Ethosuccimide Tolperizone

The mechanism of action They inhibit and limit the pathological activity of neurons in the epileptogenic sites of motor zones in subcortical regions of the brain.

Pharmacodynamics (effects) → Indications Anticonvulsant Convulsions of different origin (epilepsy, craniocerebral effect traumas, tumours of the CNS, meningitis) Side effects → Contraindications CNS inhibition, mental confusion, Activities that require attention; depression drowsiness, depression, tolerance

The principles of correct usage of : -if possible, do not apply one medicine, choose the required combination of medicines individually; -the dose of a medicine should be increased gradually; -estimate the drug effectiveness in some weeks of treatment (a number of attacks should be decreased by 50%); -if necessary, a gradual substitution of one medicine (decreasing its dose) by another one (increasing its dose) should be done; -carry out the continuous therapy (stoppage of the medicine usage is possible only in 4-5 years in the absence of pathological changes on the encephalogram).

52 The pharmacological “face” of anticonvulsants Convulsive Epileptic Medicines SE Other effects attacks: g/s status Benzobarbital +/- ++ Sedative, hypnotic Phenobarbital +/- + ++ Diazepam -/- + +++ Tranquilizing, sedative, Clonazepam +/+ + ++ hypnotic Carbamazepine +/- ++ Antidepressant, normothymic, antipsychotic, analgesic Valproic acid +/+ + Anxiolytic Ethosuccimide +/+ + Analgesic g is for great, s is for small attacks; SE is side effect.

The list of medicines INN, (Trade name) Medicinal form, dosage Benzobarbital (Benzonal) Tabl. 0.1 Carbamazepine (Tegretol, Phinlepsine) Tabl. 0.2 Clonazepam (Anthelepsine) Tabl. 0.001 Diazepam (Relanium, Sibazone) Tabl. 0.005; sol. for inj. 0.5% Ethosuccimide (Suxilep) Caps. 0.25 Phenobarbital (Luminal) Tabl. 0.1; sol. for inj. 5% Valproic acid (Convulex) Tabl. 0.2

Glossary Motor zones are sites of the cortex and subcortex, which are responsible for the organism’s motor activity. Epilepsy is a severe chronic disease manifested in the form of great and small epileptic attacks (seizures) that can be accompanied by mental, motor and autonomic nervous system disorders. An epileptogenic site is a group of neurons in the CNS that is abnormally active and generates impulses for skeletal muscles.

MEDICINES FOR PARKINSONISM TREATMENT Antiparkinsonian medicines are medicines used for treatment the Parkinson`s disease and the syndrome of parkinsonism including drug-induced parkinsonism.

Classification of medicines Anticholinergic Dophaminergic ones Antiglutamatergic ones (cholinolytic) ones Trihexiphenydil Levodopa Selegiline Nacom

The mechanism of action The mechanism of action of this group is based on modern data about pathogenesis of the Parkinson`s disease. It is known that this disease disturbs the balance of two neurotransmitters in the CNS: the amount of dophamine decreases and the content of acetylcholine increases. Antiparkinsonian medicines restore the balance between dophaminergic and cholinergic systems of the brain. By the mechanism of their action medicines are divided into:

53 I. Anticholinergic (they block central M-cholinoreceptors decreasing the effect of acetylcholine in the CNS and periphery). II. Dophaminergic (substitute the deficiency of dophamine in the CNS). III. Antiglutamatergic (decrease the stimulating effect of glutamate neurons in the CNS that develops on the background of dophaminergic system insufficiency).

Pharmacodynamics (effects) → Indications Antiparkinsonian effect Parkinson`s disease, syndrome of parkinsonism Side effects → Contraindications Anticholinergic: tachycardia, increase of IOP, Tachycardia, glaucoma paralysis of accommodation, dry mouth Dophaminergic: hypotension, arrhythmia, Disorders of the cardiac activity, development of psychoses psychoses Antiglutamatergic: convulsions, hypotension Epilepsy, hypotension All medicines should be used with short-term intervals (1-2 days per week) to prevent the appearance of tolerance.

The pharmacological “face” of antiparkinsonian medicines Medi- Antiparkinsonian effect SE Other peculiarities cines Levo- +++ ++ Dophamine predecessor, penetrates dopa (―a golden standard‖ of through the BBB. A ―off and in‖ the antiparkinsonian phenomenon is characteristic (changes of therapy) the well-being and immobile states) Nacom ++ + Composition: levodopa, carbidopa (short-term) (dopha-decarboxylase ). The effect is rapid with the less toxicity Sele- ++ + Antidepressant. It should be combined giline with nacom or levodopa Trihe- ++ ++ Cholinolytic xiphe- nydil Aman- + + Antiviral effect, tolerance tadine

The list of medicines INN, (Trade name) Medicinal form, dosage Amantadine (Midantan) Tabl. 0.1 Levodopa (Levopa) Tabl. 0.5 Nacom (Levodopa+Carbidopa) Tabl. Selegiline (Umex) Tabl. 0.005 Trihexiphenydil (Parkopan, Cyclodol) Tabl. 0.005

Glossary The Parkinson`s disease is the chronic disease of the CNS manifested by rigidity of muscles, tremor of hands and head, as well as increased salivation, perspiration, sebaceous face, irritability and the feeling of weeping. Dopha-

54 decarboxylase is an enzyme that destroys dophamine. The antiparkinsonian effect is removal of the symptoms of the Parkinson`s disease and the syndrome of parkinsonism. Rigidity is the increase of the muscular tone. The syndrome of parkinsonism is the secondary disorder of the CNS functions (with the similar symptoms of the Parkinson`s disease) that can be the result of the CNS , use of , atherosclerosis of the brain vessels and the trauma of the head. Tremor is constant and involuntary shivering.

V. MEDICINES STIMULATING THE CENTRAL NERVOUS SYSTEM (CNS )

These medicines increase excitability and restore the CNS functions when they are suppressed, increase mental and physical activity, improve mood and health. Life, capacity of work (productivity) and longevity, of a human depends on these medicines. CNS stimulants are divided into analeptics, psychomotor stimulants, , medicines, adaptogens.

ANALEPTICS

Analeptics (in Greek analepticos means ―recovery, reviving‖) are medicines stimulating inhibited vitally important centres of the medulla oblongata (respiratory and vasomotor ones) due to decrease of the excitability threshold of these centres. These are medicines of the emergency.

Medicines Caffeine sodium benzoate Ethimizole Camphor Nicethamide Cytisine Carbonic acid Sulphocamphocaine

The mechanism of action Direct-acting analeptics stimulate the respiratory and vasomotor centres directly (Caffeine, Bemegride, Ethimizole). Reflex-acting analeptics provide the reflex stimulation of the respiratory centre via chemoreceptors of the carotid sinus (Cytizine). Mixed-acting analeptics provide the reflex action through the chemoreceptors of vessels together with the direct action on the vitally important centres of the medulla oblongata (Nicethamide, Camphor, Carbonic acid).

Pharmacodynamics (effects) → Indications Analeptic: the stimulation of the Asphyxia, shock, collapse, reflex stoppage of respiratory and vasomotor centres breathing in trauma, etc. Cardiostimulating Acute , acute and chronic disorders of the blood circulation ―Awakening‖ Acute poisoning by CNS depressants: hypnotics and general anesthetics, alcohol, narcotic analgesics

55 Side effects → Contraindications Stimulation of the CNS, insomnia, Psychoses, insomnia, essential hypertension, hypertension, convulsions predisposition to convulsions

The pharmacological “face” of analeptics

Stimulation Effects

-

Medicines en Other effects

RC*/** VMC

ing”

“Awak Convulsant Caffeine +/- + + ++ As analeptic it is weaker than bemegride and nicethamide Bemegride ++++/- ++ ++++ ++++ It is effective in intoxications with OA and barbiturates Nicethamide ++/++ +++ + ++ Antipellagric Sulphocam- ++/+ ++ ++ ++ It is stronger than camphor, can phocaine be introduced i/v Ethimizole ++++/-   Spasmolytic, anti-inflammato- ry, anti-allergic, nootropic Camphor +/+ + + + Locally: irritative, anti-inflam- matory, antiseptic. Resorptively: cardiostimulating Cytisine -/++ ++ If there is no effect in 5-8 min, Carbonic acid ++++/++ it means that cytisine and carbonic acid do not act RC is a respiratory centre (* - direct, ** - reflex action); VMC is a vasomotor centre, OA are narcotic analgesics. The list of medicines INN, (Trade name) Medicinal form, dosage Bemegride Sol. for inj. 0.5% Caffeine sodium benzoate Sol. for inj. 10%, 20% Camphor Sol. for inj. 20% Carbonic acid Balloon Cytisine Sol. for inj. 0.15% Ethimizole Sol. for inj. 1.5% Nicethamide (Cordiamine) Sol. for inj. 25% Sulphocamphocaine Sol. for inj. 10% Glossary Asphyxia is a severe disorder of breathing. Hypotension is the decrease of the blood pressure. Collapse is a rapid strong decrease of the blood pressure. Awakening effect is the return of consciousness, recovery of the inhibited functions of the heart and lungs when using high doses of analeptics. Shock is the acute severe pathological process with the acute disorders of the CNS functions, blood circulation and breathing.

56 PSYCHOMOTOR STIMULANTS (PSYCHOSTIMULANTS, PSYCHOTONIC MEDICINES)

Psychomotor stimulants (psyche means ―soul‖) are medicines that increase mental and physical activity.

Classification of medicines Derivatives of xanthine phenylalkylamines sydnonimines Caffeine sodium Amphetamine sulphate Mesocarb benzoate Feprosidnine hydrochloride

The mechanism of action They increase and regulate the excitation processes in the brain cortex, promote release of catecholamines (noradrenaline and dophamine) in the CNS.

Pharmacodynamics (effects) → Indications Psychostimulating: increase of mental To increase mental and physical activity of (cognitive functions) and physical healthy people in the extreme conditions activity ―Awakening‖, analeptic Poisoning by general anesthetics, narcotic analgesics and hypnotic medicines Elimination of drowsiness Pathologic drowsiness Thymoleptic (improvement of Psychic depression (neuroses, depression, depressed mood in patients) alcoholism) Side effects → Contraindications Insomnia, increased excitability Insomnia, increased excitement, essential and irritability, hypertension, hypertension, atherosclerosis, diseases of the tachycardia cardiovascular system NB! The usage of psychomotor stimulants is contraindicated in the second half of the day, before going to bed and for aged people.

The pharmacological “face” of psychomotor stimulants Medicines BP Thymoleptic Other peculiarities Caffeine ++ It is not prescribed to children under 2 sodium years old. It potentiates the effect of OA; benzoate stimulates the gastric juice secretion; has the cardiostimulating and anti-aggregant effect, causes ―centralization‖ of the blood circulation Amphetamine +++ +++ It is a powerful of the CNS sulphate (―awakening‖ amine). It causes anorexia, euphoria, motor excitation, addiction. It is an indirect-acting adrenomimetic (dilates bronchi, pupils, etc.) Mesocarb + ++ It is less dangerous than amphetamine; there is no euphoria and excitation; moderate tachycardia

57 Feprosidnine + + Moderate antidepressant and cholinolytic hydrochloride effect, it is weaker than mesocarb

The list of medicines INN, (Trade name) Medicinal form, dosage Amphetamine sulphate Tabl. 0.01 Caffeine sodium benzoate Sol. for inj. 20% Feprosidnine hydrochloride Tabl. 0.005 Mesocarb Tabl. 0.005

Glossary Cognitive functions are higher cognitive functions including the stock of knowledge and words, ability to abstract thinking, calculation and reproduction of flat and volumetric objects.

ANTIDEPRESSANTS Depression is characterized by the following basic symptoms: depressive, dreary, worried mood, psychic and motor inhibition. These features are often accompanied by insomnia, sexual disorders, low voice, decreased efficiency of work. Disorder of neurotransmitters functions in the brain, namely the functions of serotonin (it has the leading part), noradrenaline and dophamine in less extent, is the basis of pathogenesis of depressive states. Serotonin is known to be neurotransmitter of a good mood: it improves mood, stimulates the brain’s intellectual function, takes part in regulation of appetite (decreases it), in the ―sleep-awake‖ cycle, in the sexual behaviour. Noradrenaline provides psychostimulating effect; participates in supporting of awaken state, in forming of cognitive, adaptation reactions. Dophamine provides the regulation of the motor activity and spatial orientation and it participates in the formation of memory. Antidepressants (thymoleptics) are psychotropic medicines, which remove mainly the depressive mood or depression, they can stimulate the interest to life, activity and optimism. Antidepressants are classified by their ability to affect the neurotransmitters functions and metabolism.

Classification of medicines The Ist generation (non-selective ones) Irreversible-acting Inhibitors of the Inhibitors of the receptor MAO inhibitors monoamines re-uptake action, plant origin ones* Nialamide Mianserine Doxepine Hypericine* The IInd generation (selective ones) Reversible-acting Inhibitors of the MAO inhibitors serotonin re-uptake Pyrazidol Paroxetine Sertraline The IIIrd generation (medicines with a “double” action) Venlafaxin Milnaciprane

58 The mechanism of action The common mechanism of action for all antidepressants is the increase of monoamines’ activity (noradrenaline, serotonin, dophamine) that realizes due to the inhibition of monoamineoxydase (MAO) enzyme, inhibition of the monoamines re- uptake and intensification of neurotransmitters release from the presynaptic membranes.

Pharmacodynamics (effects) → Indications Antidepressant (removal of Depression and depressive states in melancholy and depression, schizophrenia, stroke, tumours, post-traumatic worsening of memory, weakness, states, alcoholism, senile psychosis, manic- low speech, absence of emotions, depressive and climacteric psychosis, slowing down of movements) atherosclerosis Side effects → Contraindications Headache, dry mouth, dizziness, The states requiring quick psychic and physical drowsiness, decrease of attention reactions; disorders of the cerebral blood and efficiency of work circulation Hepatotoxicity, nephrotoxicity, Diseases of kidneys and liver, pregnancy, nausea, vomiting lactation

NB! The simultaneous use of MAO inhibitors with food products, which are rich in thyramine (cheese, cream, smoked food, coffee, beer, red wine, chocolate), leads to the appearance of the ―cheese‖ syndrome.

The pharmacological “face” of antidepressants

Effects

lytic Other

Medicines o

effects/peculiarities

sedative

anxiolytic

thymoleptic

cholin psychostimulating Amitriptyline +++ +++ +++ ++ Antihistaminic, analgesic, Imipramine +++ ++ +++ + decrease of libido Mianserine ++ ++  + Antihistaminic, hypnotic, anti-ulcer Doxepine ++ +++ ++ ++ Antihistaminic, analgesic, spasmolytic, anticonvulsant Pyrazidol ++ +  Nootropic Sertraline ++ ++ ++ Treatment of severe depressions. It causes sexual disorders Nialamide ++ ++ + Marked side effects

59 Milnaciprane ++ + Paroxetine ++   ++ It is a strong selective inhibitor of the serotonin reuptake

The list of medicines INN, (Trade name) Medicinal form, dosage Amitriptyline Tabl. 0.075 Doxepine (Spectra) Caps. 0.025 Fluoxetine (Prozak) Tabl. 0.02 Hypericine (Deprim) Tabl. 0.06 Imipramine (Melipramine) Tabl. 0.075 Mianserine (Lerivon) Tabl. 0.01 Milnaciprane Caps. 0.025 Nialamide (Nuredal) Tabl. 0.025 Paroxetine (Paxyl) Tabl. 0.02 Pyrazidol (Pyrlindol) Tabl. 0.025 Sertraline (Zoloft) Tabl. 0.05 Venlafaxine Tabl. 0.075

Glossary The “cheese” syndrome is the increase of blood pressure up to the hypertensive crisis. Schizophrenia (syn. the Bleuler`s disease) is the chronic progressive psychosis.

NOOTROPIC MEDICINES Nootropic medicines (noos means ―thinking, mind‖ and thropos is ―affinity‖) are medicines that improve the mental activity increasing the brain’s resistance to the damaging factors.

Medicines GABA Pyritynol Fenibute gopantenate Pyracetam

The mechanism of action Most nootropic agents are similar to GABA by their structure and the principle of action, and that is why they are called GABA-ergic medicines. GABA is not only the endogenous inhibitory mediator of the CNS, but it also takes part in metabolic processes in the brain: it increases energy and plastic processes in the CNS (increasing the biosynthesis of RNA, DNA, proteins, respiratory activity of brain’s tissues, utilization of glucose by the brain). These medicines promote the increase of the brain’s resistance to hypoxia, improvement of the blood supply in the brain and the easier elimination of toxic metabolic products from the brain. All the phenomena mentioned lead to the enhancement of the brain’s functions.

60 Pharmacodynamics (effects) → Indications Nootropic effect (improvement of Craniocerebral traumas, stroke, mental memory, speech, learning; increase of retardation in children, senile , the brain’s resistance to hypoxia and disorders of memory, attention, speech; intoxication, decrease of dizziness, atherosclerosis, encephalopathy headache, drowsiness, apathy) Side effects → Contraindications Insomnia, irritability, nausea Disorders of sleep, neurosis, pregnancy

The pharmacological “face” of nootropic medicines

Effects

-

Medicines - Other peculiarities

sycho

lating

stimu

p sedative Pyracetam + The reference medicine. The stressprotective, adaptogenic effects. It increases the effect of anti- anginal medicines Pyritynol ++ + Antidepressant, anti-asthenic Calcium + + Anticonvulsant, analgesic; it has a low toxicity, gopantenate increases the action of barbiturates and anticonvulsants GABA + Hypotensive, anticonvulsant effects Fenibute + Tranquilizing and antipellagric effect, it potentiates the effect of CNS depressants

The list of medicines INN, (Trade name) Medicinal form, dosage Calcium gopantenate (Pantogam) Tabl. 0.02 Fenibute Tabl. 0.25 GABA (Aminalon, Gammalon) Tabl. 0.25 Pyracetam (Nootropil) Tabl. 0.2 Pyritinol (Encephabol) Tabl. 0.2

Glossary Stroke is the acute disorder of the blood circulation in brain or in spinal cord resulting in the disorders of the CNS functions.

ADAPTOGENS Adaptogens are medicines of plant and animal origin that have the general tonic action on the CNS functions, the endocrine system and metabolism. They increase organism’s resistance to the unfavourable environmental factors. These medicines promote the changes in the organism, thanks to them it adapts better to changing conditions of the environment and that is why these medicines are called adaptogens. Unlike other CNS stimulants adaptogens do not have the stimulating effect with their first administration.

61 Classification of medicines Medicines of plant origin Medicines of animal and synthetic* origin root tincture Schizandra tincture Pantocrine Aralia tincture Leuzea extract Citrullin* Eleutherococcus extract Toniphyt

The mechanism of action They stimulate non-specific resistance of the body, the synthesis of RNA and proteins in cells, improve the recovery processes and the activity of energy metabolism enzymes, reduce the catabolism of carbohydrates, proteins, fats leading to the ―economization‖ of metabolism and the organism’s adaptation to the unfavourable conditions.

Pharmacodynamics (effects) → Indications Adaptogenic effect: improvement of Increase of the work efficiency of healthy the mental, physical activity and the people working in unusual climatic organism’s resistance to a great conditions (the North, tropics, etc.); with number of negative factors static, functional (hearing, vision, etc.), (exhausting physical work, hypoxia, dynamic loadings; in sportsmen, elderly infections, etc.); stimulation of the people. Prophylaxis of infectiousl and non- cardiovascular system. Unlike infectious diseases, as well in the period of psychomotor stimulants the effects reconvalescence. The treatment of asthenic of adaptogens reveal slowly states, neuroses, hypotension, increased drowsiness Side effects → Contraindications Stimulation of the CNS, The increased excitability of the CNS, neuroses, insomnia, hypertension insomnia, hypertension NB! To avoid the disturbance of sleep adaptogens should not be administered in the evening.

The pharmacological “face” of adaptogens Medicines Peculiarities Ginseng root tincture  the level; a substitute – ―Bioginseng‖ Aralia root tincture Antihypoxic effect Eleuterococcus extract A liquid and dry extract is manufactured Leuzea extract liquid  the protein synthesis Schizandra tincture It stimulates the cardiovascular and respiratory systems Toniphyt It contains 7 plants. The spasmolytic effect, increases appetite Pantocrine It is an extract of the stag’s antlers. It has a tonic effect on the CNS, the GIT and skeletal muscles

The list of medicines INN, (Trade name) Medicinal form, dosage Aralia root tincture Tinct. 50 ml

62 Citrullin (Stimol) Sol. 50% Eleuterococcus extract Extr. 50 ml Ginseng root tincture Tinct. 50 ml Leuzea extract liquid Extr. 40 ml Pantocrine Extr. 50 ml, tabl. 0.15 Schizandra tincture Tinct. 50 ml Toniphyt Pack 100.0

Glossary Adaptation is the organism’s accommodation to the changed conditions of its existence. Asthenia is the increased fatiguability with the change of mood, weakness, irritability, sleep disorders, etc. Hypotension is the decrease of the blood pressure. Catabolism is disintegration of tissue and cell elements, as well as splitting of carbohydrates, fats and proteins for energy or plastic providing of the life activity processes. Reconvalescence is the recovery of the organism’s normal life activity after a disease.

VI. MEDICINES AFFECTING THE CARDIOVASCULAR SYSTEM

CARDIOTONIC MEDIСINES

Cardiotonic medicines are medicines that intensify the myocardial contractility and eliminate the symptoms of heart failure (cardiac insufficiency). Cardiac glycosides are the most widely used in treatment of heart failure (HF). To understand the effects of cardiotonic medicines it is necessary to know that HF is developed when the heart loading does not correspond to the ability of the heart to perform its work and it is connected, first of all, with the myocardial contractility. There is the acute and chronic HF. The latter has compensated and decompensated forms. In the first case the heart incapability to provide normal blood circulation in the organism is compensated by its hypertrophy, especially one of the left ventricle. By further progressing of the disease the compensatory mechanism is exhausted and cardiac insufficiency comes into the decompensation stage characterized by tachycardia, increase of the circulating blood volume, increase of the venous pressure, hemostatic phenomena in the systemic circulation, the lower extremities edemas, as well as cyanosis and dyspnea. Tachycardia and dyspnea develop as compensation of hypoxia. Cyanosis is caused by hypoxia. Cardiac glycosides (CGs) are basic medicines for the HF correction – they increase the myocardial productivity providing its economical but effective work. CGs are contained in different types of Digitalis, Strophanthus, Adonis, Convallaria and other medicinal plants.

Classification of medicines Medicines of Digitalis Strophanthus Convallaria, Adonis* Digoxin Lantoside Strophanthine G Corglycon Adoniside* Digitoxin

63 The mechanism of action The level of free calcium in the cardiomyocyte plays an important role in providing the heart muscle contractility. In the cell calcium binds to the protein troponin, which changes its spatial conformation and releases the contractile proteins (actin and myosin) interacting to each other with the formation of actomyosin, that it leads to the contraction of the muscular fibres. The mechanism of the positive inotropic effect of the CGs is connected with their ability to increase the content of Ca2+ ions in the cardiomyocytes mainly due to the blockade of SH-groups of Na+,K+-ATP-ase enzyme. The increase of the Ca2+-ions concentration leads to the increase of the contractile proteins activity and as a consequence to the increase of the heart contraction force. More powerful contractions of the heart push the blood out of its cavities more completely, the residual blood volume and the myocardial tension decrease, and as a result the energy loss for its contraction also decreases. The decrease of the conductivity inside the heart, the negative dromotropic effect, and the increase of excitability of the myocardium, the positive batmotropic effect, is based on the same mechanisms of the CGs action. The negative chronotropic effect (the diastole’s prolonging) occurs due to the delay of the change of the cardiomyocyte cell membrane functional states (inhibition of the polarization and depolarization processes of the atrioventricular node cell membranes and difficulty of the potassium return into the cell). The increase of the diastole’s time promotes the delivery of oxygen and essential nourishing substances to the heart muscle. The biochemical mechanism of the CGs action in HF is stipulated by their trophic effect: the values of energy, carbohydrate, protein, lipid and electrolyte metabolism are normalized. The effect of CGs is considered as a result of the systemic and renal blood circulation normalization.

Pharmacodynamics The main effect in pharmacodynamics of CGs is the cardiotonic effect, which consists of 4 components: 1. The positive inotropic effect: the systole becomes more powerful and shorter and it leads to the increase of the cardiac output (the beat and minute blood volume). 2. The negative chronotropic effect: the diastole’s prolonging and the cardiac rhythm delay. The heart has an opportunity for more complete ―rest‖. The heart rate delay promotes the improvement of the metabolic processes in myocardium and the more complete blood supply of the heart’s cavities. 3. The negative dromotropic effect: the decrease of the impulse conducting through the heart’s conductive system. 4. The positive batmotropic effect: the increase of the myocardial excitability. Thus, due to the cardiotonic effect CGs normalize the main blood circulation values: the beat and minute blood volume increases, the venous pressure decreases (i.e. preload); the blood circulation speed increases, the volume of the circulating

64 blood decreases. The phenomena of hypoxia weaken and disappear, the symptoms of cardiac insufficiency – dyspnea, cyanosis – decrease. The positive action of CGs is their ability to increase the efficiency of the heart: under the influence of CGs the heart works more, but at the same time its oxygen consumption does not increase, i.e. it works more economically. The cardiotonic effect of CGs differs from the cardiostimulating effect of epinephrine, ephedrine, isoprenaline and analeptic medicines (caffeine, nicethamide, etc.) by the effect over the myocardial energy processes: CGs promote the accumulation of the energy in the heart muscle, and cardiac stimulants waste energy and their prolonged application leads to the myocardial exhaustion and dystrophy. Besides, unlike cardiotonics cardiac stimulants increase the heart rate, i.e. have a positive chronotropic effect, and it increases the energy consumption too. That is why cardiac stimulants are administered during a short period of time as symptomatic medicines for the myocardial function normalization when it is inhibited by toxic substances. CGs are used as medicines for pathogenetic and often prolonged therapy.

Indications Chronic and acute HF, tachyarrhythmias. Sometimes CGs are indicated as prophylaxis for preventing HF in pathological states that cause it (pneumonias, toxicoses, severe hypertension and heart rheumatic dysfunctions).

Pharmacokinetics CGs consist of a non-saccharine part (aglycone or genine) and a saccharine part. The cardiotonic effect of these medicines is connected with aglycone. The main chemical structure of aglycone is cyclopentan-perhydrophenantren nucleus bound to the unsaturated lactone ring. The saccharine part affects the glycosides solubility, their absorption, bioavailibility and other pharmacokinetic peculiarities. So, by the solubility CGs are divided into lipophylic (Digitoxin), hydrophylic (Strophanthine), mixed hydrophylic and lipophylic (Digoxin, etc.). Lipophylic CGs are well absorbed from the GIT and bound actively to blood plasma proteins, they are eliminated slowly and accumulate. They are introduced perorally and are used in chronic HF. Hydrophylic CGs are absorbed poorly from the GIT and are not almost bound to plasma proteins, they are eliminated quickly and do not accumulate. They are introduced parenterally and are used in acute HF. Lipophylic and hydrophylic CGs have an intermediate position by their physical and chemical properties and that is why they can be introduced both perorally and parenterally.

Principles of correct usage Therapeutic tactics of the glycoside treatment includes two phases: Digitalization (the saturation phase) can be fast, middle and long, it lasts from 1 till 5 or more days. The medicine is administered until the marked therapeutic effect without the symptoms of intoxication is achieved. The twenty-four hours dose of digitalis medicines is 2-2.5 mg, the dose of strophanthus medicines is 0.6-1 mg. Maintaining (supporting) phase provides stabilization of the achieved level of the therapeutic effect by prescribing a medicine in the maintaining dose (supporting a stable concentration in blood).

65 Side effects Disorders of the heart conductivity and rhythm: bradycardia, up to the heart stoppage, arrhythmia. Worsening of the myocardial contractility. Increase of HF symptoms, retrosternal pain, myocardial ischemia. Neuritis of the optic nerve (the change of normal vision).

Contraindications Glycoside intoxication, shock, marked bradycardia, ventricular extrasystolia, ischemic heart disease.

The pharmacological “face” of CGs Medicines Route of administration Absorption in

intravenously perorally - the GIT

Start Duration Start Duration u mulation (min) (days) (hours) (days) Acc Digoxin 15-40 5-6 1.5-3 5-6 + + Digitoxin 2-4 14-21 ++ + Lantoside 10-30 5-7 1-2 5-7  + Strophanthine G 5-10 2-3 Corglycon 5-10 3-4 Adoniside 15-40 3-4 +

The list of medicines INN, (Trade name) Medicinal form, dosage Adoniside Sol. 15 ml Corglycon Sol. for inj. 0.06% Digitoxin Tabl. 0.0001; supp. 0.00015 Digoxin Sol. for inj. 0.025%; tabl. 0.0001 Lantoside Tabl. 0.00025 Strophanthine G Sol. for inj. 0.05%

Glossary Atrioventricular node is one of the drivers of the heart’s rhymth, the part of its conductive system. Cardiomyocyte is a cell of the myocardium. Preload is the pressure to the heart’s valves in the venous return of blood towards the heart.

ANTIHYPERTENSIVE MEDICINES (HYPOTENSIVE MEDICINES)

These are medicines that decrease the blood pressure and are used for treatment hypertension or symptomatic arterial hypertension. The BP value depends on the vascular wall elasticity, total peripheral vascular resistance (TPVR), the heart and kidneys work. The object of the pharmacological affection of hypotensive medicines is different links of the vascular tone regulation mechanism, which include pressor (vasoconstrictive) and depressor (vasodilating) components that are worked with the help of the neurohormonal factors.

66 Neurohormonal factors of the vascular tone regulation Vasoconstrictors Vasodilators constrict vessels dilate vessels Adrenaline Noradrenaline Nitrogen monoxide (NO) Angiotensin II Vasopressin (ADH) Acetylcholine Histamine Dophamine

The mechanism of action of antihypertensive medicines is connected with their influence on different links of the blood pressure regulation (fig. 6): - upon the nervous system: brain cortex, hypothalamus, vasomotor centre, autonomic ganglia, sympathetic postganglionic nerves and adrenoreceptors; - out the nervous system (peripheral vasodilating medicines): smooth muscles of the vascular wall, myocardium, endocrine system, renal diuresis, tissue metabolism. Medicines for treatment hypertension are classified considering all these facts.

Classification of medicines Medicines decreasing Direct- and indirect-* Medicines for complex the activity of the acting vasodilators without treatment of nervous system the influence on the hypertension sympathetic part sympathetic nervous Central-* and system tone (peripheral peripheral-acting vasodilating medicines) 1. Stimulants of central 8. Calcium antagonists 14. α2-adrenoreceptors* 9. Inhibitors of ACE* 15. CNS depressants 2. Selective agonists of 10. Blockers of angiotensin imidazoline receptors* receptors* 3. β -adrenoblockers 11. Activators of potassium 4. α - adrenoblockers canals* 5. α + β adrenoblockers 12. Peripheral vasodilators 6. Ganglionic blockers 13. Myotropic spasmolytics 7. Sympatholytics

Medicines decreasing the activity of the nervous system sympathetic part

Classification of medicines Agonists of cent- Sympatholytics* β-adrenoblockers α 1- and α + β *- ral α 2-adreno- and and ganglionic (cardioselective* adrenoblockers imidazoline* blockers and non- receptors cardioselective) Clonidine Reserpine* Atenolol* Prazosine hydrochloride Hexamethonium Bisoprolol* Doxazosine Methyldopha benzosulphonate Propranolol Labethalol* Moxonidine*

The mechanism of action The mechanism of action of central α2-adrenomimetics is connected with stimulation of presynaptic α2-AR of the vasomotor centre causing the inhibitory effect on the vasomotor centre of the medulla oblongata. It causes decrease of the central

67 sympathetic influence on arteries and heart. Agonists of imidazoline receptors stimulate the latter ones in the vasomotor centre inhibiting catecholamines release and their influence on the cardiovascular system. Sympatholytics alter the synthesis and accumulation of catecholamines in the vesicles and it promotes decrease of the mediators reserve (noradrenaline, adrenaline and dophamine) in the presynaptic endings of neurons and decrease of the vasoconstrictive effect of catecholamines. β- adrenoblockers blocking β1-AR decrease the cardiac output and systolic pressure, as well as the heart rate and it leads to the BP decrease. The inhibition of renin release is also important in the mechanism of the antihypertensive action of β-adrenoblockers and it leads to the decrease of angiotensin II and production, the decrease of the TPVR and retention of sodium and water in the organism. α1-adrenoblockers block α1-AR of the peripheral vessels, and it leads to their dilation and decrease of BP. The mechanism of the hypotensive action of ganglionic blockers is connected with disorder of vasoconstrictive impulses transmission through the sympathetic ganglia.

Pharmacodynamics (effects) → Indications Hypotensive effect Hypertension, hypertensive crisis Medicines have the hypotensive, as well Prevention and treatment of angina as anti-anginal, anti-arrhythmic effect at pectoris, tachyarrhythmia, hypertension the same time (β-adrenoblockers) Side effects → Contraindications Headache, dizziness, depression, Atherosclerosis of the cerebral vessels, orthostatic hypotension, bradycardia, depression, severe heart failure, diseases dyspepsia of the GIT

The list of medicines INN, (Trade name) Medicinal form, dosage Atenolol Tabl. 0.1 Bisoprolol (Concor, Coronal) Tabl. 0.01 Clonidine hydrochloride (Clofeline) Tabl. 0.00075 Doxazosine (Cardura) Tabl. 0.002 Hexamethonium benzosulphonate (Benzohexonium) Tabl. 0.1 Labetalol Tabl. 0.1 Methyldopha (Dopegit, Methyldopa) Tabl. 0.25 Moxonidine (Cint) Tabl. 0.0002 Prazosine (Adverzuten) Tabl. 0.002 Propranolol (Anaprilin, Pranolol) Tabl 0.01 Reserpine (Rausedil) Tabl. 0.1

Glossary Angiotensin II is a vasoconstrictive polypeptide that increases the BP. Hypertension is a chronic disease of the cardiovascular system that is characterized mainly by a stable high BP. Hypertensive crisis is exacerbation of hypertension. Hypotensive (antihypertensive) effect is the BP decrease. Catecholamines are a group of physiologically active substances of the similar chemical structure that are

68 mediators (noradrenaline, dophamine) and hormone (adrenaline). Total peripheral vascular resistance is the resistance of peripheral vessels to the blood flow (tone of vessels). Cardiac output is the volume of blood that is thrown out by the heart per one constriction; the heart constrictive function value.

Peripheral vasodilating medicines

Classification of medicines Peripheral Inhibitors of ACE Blockers of vasodilators and and antagonists of calcium canals Spasmolytics activators of angiotensin (calcium potassium canals* receptors* antagonists) Hydralasine h/chl. Enalapril Bendazole Lisinopril Papazole Sodium Captopril Magnesium nitroprusside Potasium losartane* h/chl. sulphate * Valsartane* Dilthiazem Papaverine h/chl.

The mechanism of action Peripheral vasodilators and myotropic spasmolytics relax the smooth muscles of the peripheral vessels, that it is connected to their direct myotropic action on the vascular wall. A principle of the hypotensive effect of potassium canals activators is as follows: the potassium canals open and the K+ ions leave the cell  the Ca2+ ions come into the cell in less amount  the smooth muscles tone of vessels decreases  vessels dilate  the BP decreases. Inhibitors of ACE block the angiotensin-converting enzyme and, thus, block the transformation of angiotensin I into angiotensin II that is an endogenous vasopressor substance (it constricts vessels, increases the production of aldosterone and vasopressin, promotes development of vascular ―rigidity‖ and stimulates the sympathetic innervation). Inhibitors of ACE decrease the sympathetic system activity, inhibit the hypertrophy process of vascular muscles and the myocardium. Antagonists of angiotensin II receptors block angiotensin II receptors of vessels and it also leads to elimination of angiotensin II effects (including its stimulating effect on the release of aldosterone and activation of the sympathetic nervous system) and decrease of the BP. Calcium canals blockers block free transport of calcium ions in the muscular fibres. Disorder of calcium ions penetration inside the muscular cells leads to decrease of the vascular tone and decrease of the BP.

Pharmacodynamics (effects) → Indications Hypotensive effect (all medicines Hypertension and hypertensive crisis decrease BP and TPVR, dilate arteries) Decrease of post-load and/or pre-load to Hypertension in combination with the heart angina pectoris (calcium antagonists). Chronic HF (inhibitors of ACE, antagonists of angiotensin II receptors) Spasmolytic effect (myotropic Spasms of the smooth muscles of the spasmolytics) internal organs Moderate immune-stimulating effect Decrease of immunity (Bendazol)

69 Side effects → Contraindications Headache and hypotension up to collapse; Hypotension, marked cardiac, hepatic HF and renal insufficiency

The pharmacological “face” of hypotensive medicines Medicines Application in Effect in hypertensive Effect to hypertension crisis the heart medium severe start, min duration, h load Clonidine + 15-20 4-8 Reserpine + Hexamethonium 1-5 4-6 Sodium nitroprusside + 1-5 2-5 min pre/post Diazoxide + 1-2 4-12 post Hydralasine + + 20-40 3-6 post Enalapril + + 30 2-4 pre/post Lisinopril + + pre/post Potassium losartane + + 60 24 post Calcium antagonists + + 20 3-6 post β -adrenoblockers + post Spasmolytics +

The list of medicines INN, (Trade name) Medicinal form, dosage Amlodipine (Norvask, Amlocor) Tabl. 0.001 Bendazole (Dibazole) Tabl. 0.002; sol. for inj. 1% Captopril Tabl. 0.025 Diazoxide Sol. for inj. 1.5% Dilthiazem (Diacordine) Tabl. 0.06 Enalapril (Ednit, Enap) Tabl. 0.01 Hydralasine h/chl. (Apressine) Tabl. 0.01 Isradipine (Lomir) Caps. 0.001; sol. for inj. 0.01% Lisinopril (Dirotone) Tabl. 0.002 Magnesium sulphate (Cormagnesine) Sol. for inj. 25% Minoxidil (Depressan) Tabl. 0.005 Nifedipine (Corinfar) Tabl. 0.01; sol. for inj. 0.01% Papaverine h/chl. (Papavin) Tabl. 0.01; sol. for inj. 2% Papazole (papaverine h/chl. + bendazole) Tabl. Potassium losartane (Kozaar) Tabl. 0.05 Sodium nitroprusside Pwd. for inj. 0.025 Valsartane (Diovan) Caps. 0.06 Verapamil h/chl. (Isoptine, Finoptine) Tabl. 0.04

Glossary Angiotensin-converting enzyme (ACE) is an enzyme that promotes convertion of angiotensin I into angiotensin II. Hypertrophy is the tissue’s overgrouth. Myofibril is the muscle’s fibre.

70 ANTI-ANGINAL MEDICINES

Ischemic heart disease (IHD) or coronary heart disease – stenocardia (angina pectoris) and myocardial infarction – is the imbalance between the oxygen consumption by myocardium and its supply in oxygen along the coronary vessels, and it is accompanied by the development of the myocardial hypoxia and accumulation of partially oxidized products of metabolism that irritate receptors and cause pain. The heart supply with oxygen depends, first of all, on the state of the coronary circulation. That is why the object of the pharmacological affection on the IHD pathogenesis is the regulation mechanisms of the tone of large and small (especially arterioles) cardiac vessels, which provide the coronary circulation; as well as the decrease of the myocardium need in oxygen; providing the normal metabolism in the myocardium, the level of and prothrombin in blood and intravascular thrombocyte aggregation. In the therapy of IHD the decrease of oxygen consumption by the myocardium is achieved by different ways: firstly, by decreasing the load on the myocardium, secondly, by decreasing the heart’s work. The heart load can be decreased by dilation of veins and arteries, which leads to the decrease of the venous blood return towards the heart (decrease of the heart pre-load) and the decrease of the total peripheral vascular resistance (TPVR) (decrease of the heart post-load). The decrease of pre- and post-load reduces the oxygen consumption by myocardium. The heart work (the cardiac output value and rhythm) decreases when the adrenergic innervation (by β- adrenoblockers) decreases or the Ca2+ ions transport into the myocardial cells (calcium canals blockers) is inhibited. As a result of reducing of the myocardial contractility its need in oxygen decreases. The increase of oxygen delivery to the myocardium is reached due to the improvement of the coronary circulation and the myocardium oxygenation by the dilation (by direct or indirect way) of coronary vessels. It is important to improve the trophism and metabolism of the myocardium, as well as to improve the rheological blood properties in the IHD therapy. Anti-anginal medicines are medicinal agents that decrease the oxygen consumption by myocardium increasing its delivery; they optimize the energy metabolism in the myocardial cells. Antianginal medicines stop or prevent attacks of angina and acute myocardial infarction, increase the patients’ tolerance to physical loads. Classification of medicines Medicines decreasing oxygen consumption by Medicines decreasing myocardium and increasing oxygen delivery to the oxygen consumption by myocardium myocardium Calcium canals blockers (organic nitrates) (phenylalkylamines*,benzothi- β-adrenoblockers azepines**, dihydropyridines), (β1, β1+ β2*) different medicines Glycerol trinitrate Nifedipine Amiodaron Atenolol Isosorbide dinitrate Amlodipine Metoprolol Verapamil* Dilthiazem** Bisoprolol Propranolol*

71 Medicines increasing the oxygen delivery to the Medicines improving the myocardium (coronarolytics) metabolism in myocardium Carbocromen Dipyridamol Trimethasidine Menthol in bromisovalerianate Inosine

The mechanism of action The discovery of ERF (endothelium relaxing factor) or NO (nitrogen monoxide) was a great contribution to understanding the mechanisms of therapeutic effect of organic nitrates (fig. 3).

Fig. 3. The mechanism of the anti-anginal effect development by nitrates.

The coronary vessels spasm is supposed to be conditioned mainly by insufficient formation of the endogenous nitrogen monooxide (NO) by the vessels’ endothelium or by the increase of its destruction. In these cases organic nitrates substitute NO deficiency in the vascular wall. As a result, it leads to the calcium level decrease in the cells, then coronary and peripheral vessels dilation and heart’s work decrease increasing blood supply of the myocardium. Calcium antagonists (calcium canals blockers) block a slow transmembrane flow of calcium into cardiomyocytes. Blockade of calcium canals is accompanied by the decrease of the heart’s work with slowing its rhythm down, coronary and peripheral arteries dilation (decrease of BP and TPVR), as a result the myocardium need in oxygen decreases and its supply increases. β-adrenoblockers remove the sympathoadrenal influence on the myocardium and decrease the heart’s work. Amiodaron blocks α- and β-AR, calcium and sodium canals non-competitively and it leads to the decrease of the heart rate, cardiac output and coronary vessels dilation. Validol dilates coronary vessels by

72 reflex and increase the oxygen supply to the myocardium by irritating the mouth mucous membrane receptors. Carbocromen and dipyridamol inhibit phosphodiesterase and adenosindesaminase enzymes, respectively, and it leads to the coronary vessels dilation. Trimethasidine provides transmembrane transfer of the sodium, calcium, potassium ions, supports the homeostasis in cardiomyocytes. Inosine increases the energy metabolism in the myocardium.

Pharmacodynamics All medicines have the anti-anginal effect: they cause a negative inotropic effect to the myocardium and some of them have the negative chronotropic effect as well; promote the decrease of the oxygen consumption by the myocardium and the increase of the oxygen delivery. Coronarolytics have the coronarodilating effect. Dipyridamol has also the anti-aggregant effect. Trimethasidine and inosine improve metabolism in the myocardium.

Indications Removal and prevention of attacks of stable and unstable angina pectoris, acute myocardial infarction (MI), recovering therapy after MI. The complex therapy of acute and chronic HF. Prophylaxis of the hypercoagulation syndrome

(dipyridamol).

Side effects Side effects of organic nitrates are pulsatory, bursting headache; orthostatic hypotension and reflex tachycardia; the feeling of fever, facial skin reddening. Tolerance (the decrease of effect duration and strengh due to regular administration of nitrates). The syndrome of abrupt discontinuation (it reveals by worsening the symptoms of stenocardia in 1-2 days after stopping the medicines intake). When using β-adrenoblockers disorders of heart rhythm and conductivity such as bradycardia, arterial hypotension, HF and bronchospasm can appear. Side effects of calcium canals blockers are dysfunctions of the heart rate, hypotension, decrease of the myocardial contractility; amiodaron causes the muscular weakness, bradycardia, hyperthyroidism; dipyridamol causes the ―stealing‖ syndrome, hypotension; inosine causes the tachycardia, exacerbation of gout; trimethasidine causes the pain in the epigastrium; carbocromen causes bradycardia; the side effects of validol are lacrimation and dizziness.

Contraindications Anti-anginal medicines are contraindicated in the marked hypotension. Nitrates are not used in the close-angle glaucoma, epilepsy, cerebral forms of hypertension and cerebral bleedings. The absolute contraindications for using calcium canals blockers are cardiogenic shock, severe congestive HF, the acute period of MI, heart blockade, hepatic and renal insufficiency. β-adrenoblockers are contraindicated in the congestive HF, bradycardia, bronchospasm; amiodaron is not used in hypokalemia, weakness of the sinus node; dipyridamol is not used in the severe sclerosis of coronary vessels; inosine is not administered in gout; trimethasidine is not used in pregnancy; carbocromen is not administered in peptic ulcer, diseases of liver and kidneys, and atherosclerosis.

73 The pharmacological “face” of nitrovasodilators The route of Effect Medicinal Medicine R/P administration Start, min Duration, h form Glycerol sublingually 1-2 0.5 +/- Tabl., caps., trinitrate sol. (Nitroglycerine) Trinitrolong* buccally 2-3 3-5 +/+ Films Suctac forte* perorally 20-30 4-6 -/+ Tabl. Isosorbide sublingually, 3-10 1-2 /+ Tabl. dinitrate perorally 20-50 3-6 Nitroointment* transdermally 15-60 3-8 -/+ Ointment Nitroderm* 60-120 24 -/+ Plaster R-removal, P-prevention of the anginal attack; * - medicinal forms of nitroglycerine.

The pharmacological “face” of calcium antagonists (A) and β-adrenoblockers (B) Effect

Medicines T1/2, h hypotensive anti-anginal anti-arrhythmic Group Nifedipine (I) 4 +++ +++ + A Amlodipine (III) 35-50 ++ +++ + Verapamil (I) 6 ++ +++ ++ Atenolol 6-9 +++ +++ +++ B Metoprolol 3-7 +++ +++ +++ Propranolol 2-5 ++ +++ +++ I, III –generations of calcium canals blockers.

The list of medicines INN, (Trade name) Medicinal form, dosage Amlodipine (Norvask) Tabl. 0.01 Amiodaron (Cordaron) Tabl. 0.2; sol.for inj. 5% Atenolol Tabl. 0.1 Bisoprolol (Coronal) Tabl. 0.005 Carbocromen (Intencordine) Tabl. 0.075 Dilthiazem (Diacordin) Tabl. 0.06 Dipyridamol (Curantil) Tabl. 0.05; sol. for inj. 0.5% Glycerol trinitrate (Sustac forte, Nitroglycerine, Tabl. 0.00025 Trinitrolong, Nitroointment, Nitroderm) Isosorbide dinitrate (Isoket) Tabl. 0.01 Inosine (Riboxine) Tabl. 0.2; sol. for inj. 2% Menthol in bromisovalerianate (Validol) Caps. 0.1 Metoprolol (Corvitol) Tabl. 0.1 Nifedipine (Corinfar) Tabl. 0.01; sol. for inj. 0.01% Propranolol (Anapriline, Pranolol) Tabl. 0.01; sol. for inj. 1%

74 Trimethasidine (Preductal) Tabl. 0.02 Verapamil (Finoptine, Lekoptine) Dr. 0.04

Glossary Anti-anginal effect is the removal of the IHD symptoms. Myocardial infarction is necrosis of the myocardium part. Cardiomyocyte is the myocardial cell. The “stealing” syndrome is redistribution of blood from ischemiazed sites to the healthy myocardium parts caused by dipyridamol and it worsens the symptoms of IHD.

ANTI-ATHEROSCLEROTIC MEDICINES Anti-atherosclerotic medicines are medicines that decrease the level of cholesterol and atherogenic lipoproteins in blood, prevent the lipids deposition in the vascular wall, inhibit the growth of atherosclerotic plaques and cause the angioprotective effect. It is known that there is an increased level of lipids and lipoproteins in blood (hyperlipidemia) in atherosclerosis. The main classes of lipoproteins are: -lipoproteins of a very low density (LPVLD) (atherogenic) that are synthesized in the liver and they serve for transport of the endogenous triglycerides (TG) into the liver, where LPLD are produced from them; -lipoproteins of a low density (LPLD) take part in transport of cholesterol (ChS) into the cells (atherogenic); -lipoproteins of a high density (LPHD) participate in transport of ChS from tissues to the liver, where its catabolism occurs (anti-atherogenic). LPHD have the ability to block aggregation of thrombocytes and it is also important for prevention of atherosclerosis development. While interacting with lipoproteid receptors of vessels ChS and TG are released from atherogenic lipoproteins (LPVLD and LPLD), they deposit in the vascular intima and it promotes to development of atherosclerosis. The increase of the LPHD concentration prevents atherosclerotic destruction of vessels due to isolation of ChS from arterial walls. The main aim of prevention and treatment of atherosclerosis and its complications is to decrease of atherogenic lipoproteins (LPVLD and LPLD) content in blood and to increase the level of anti-atherogenic lipoproteins (LPHD). For this aim medicines that inhibit the synthesis of ChS in the liver, decelerate its absorption in the intestine, promote its transformation into bile acids, steroid hormones and vitamin D3 or accelerate ChS elimination from the organism are used. Anti-atherosclerotic medicines protect the vascular wall directly or indirectly from development of the atheromatous process in it, i.e. they are angioprotectors. Besides, in atherosclerosis antioxidants and medicines that correct the rheological blood properties ( and others) are used.

Classification of medicines Hypolipidemic medicines Sequestrants of and Antioxidants Anticoagulants bile acids others* Lovastatin Cholestiramine Phenofibrate Tocoferol Heparin Simvastatin Cyprofibrate Nicotinic acid*

75 The mechanism of action By the mechanism of action anti-atherosclerotic medicines are divided into: I. Decreasing mainly the content of ChS in blood: - Inhibitors of the ChS synthesis (statins). Statins inhibit the synthesis of ChS in the liver from the mevalonic acid. - Medicines increasing the elimination of bile acids and ChS from the organism (sequestrants of bile acids). Sequestrants of bile acids bind to ChS, TG and bile acids in the small intestine forming complexes, which are non-absorbable in the GIT. II. Decreasing mainly the content of TG in blood: derivatives of the fibroic acid (fibrates). Fibrates increase the lipoproteinlipase activity. III. Decreasing the content of ChS and TG in blood: the nicotinic acid. It decreases the release of free fatty acids and their coming into the liver and it leads to decrease of the biosynthesis of TG in the liver and formation of lipoprotein residues. IV. Antioxidants. Medicines inhibit the processes of peroxide oxidation of lipids and it leads to decrease of atherogenic lipoproteins formation and destruction of the vascular wall. V. Anticoagulants. They inhibit the process of blood at all the stages, improving the rheological blood properties.

Pharmacodynamics  Indications Anti-atherosclerotic effect Atherosclerosis, hyperlipidemia Side effects  Contraindications Headache, giddiness, muscular atrophy Pregnancy, lactation, child age, and pain, nephropathy, anaemia, myopathies; liver, kidneys and blood hepatitis, thrombocytopenia diseases

The pharmacological “face” of hypolipidemic medicines Alternative of Primary Severe ChS ChS Medicines choice HL HL absorption synthesis I II Lovastatin + + + + Simvastatin + + + + Phenofibrate + + + + Cyprofibrate + + + + Cholestiramine + + + HL – hyperlipidemia; I, II – the therapy line.

The list of medicines INN, (Trade name) Medicinal form, dosage Cholestiramine (Cholestipol) Tabl. 1.5 Cyprofibrate (Lipanor) Caps. 0.1 Heparin Sol. 5000 IU/ml Lovastatin (Mevacor) Tabl. 0.01 Nicotinic acid (Vitamin PP) Tabl. 0.1 Phenofibrate (Lipantil) Caps. 0.1

76 Simvastatin (Zocor) Tabl. 0.01 Tocoferol (Vitamin E) Caps. 0.1

Glossary Myopathy is any pathologic state of the muscular tissue, mainly the skeletal muscles. Triglycerides, cholesterol are products of the lipid metabolism.

ANTI-ARRHYTHMIC MEDICINES Anti-arrhythmics are medicines that normalize the rate and contractions of the heart preventing or removing arrhythmias. The properties of the myocardium that provide the cardiac rhythm (automatism, excitability and conductivity) depend on the electrolyte metabolism, mainly on the K+, Na+, Ca2+, Mg2+ exchange. K+ is an intracellular ion, its deficiency leads to the development of tachycardia and its excess causes bradycardia (decrease of excitability and conductivity). Ca2+ promotes the increase of the myocardial excitability, conductivity and contractility. K+ and Mg2+ are antagonists of Ca2+.

Classification of medicines Medicines removing tachyarrhythmias bradyarrhythmias Membrane- β-adreno- Prolongers of repolarization, M-cholinoblockers, stabilizers blockers calcium canals blockers*, β-adrenomimetics* K+-containing medicines** Atenolol Amiodaron Atropine sulphate Procainamide Propranolol Verapamil* Isoprenaline* Lidocaine Metoprolol Potassium and magnesium Dobutamine* asparaginate**

The mechanism of action Membrane-stabilizing medicines prevent Na+, K+, Ca2+ transport through the membranes of cardiomyocytes, slow down depolarization and repolarization. β- adrenoblockers block β1-AR of the myocardium, decrease the myocardial automatism and conductivity. Amiodaron is a medicine of the combined action: it slows down the repolarization blocking potassium, sodium and calcium canals; possesses the non-competitive β-adrenoblocking effect. Calcium canals blockers (or calcium antagonists) inhibit the Ca2+ transport through slow L-calcium canals retarding the spontaneous depolarization of the myocardial cells and decreasing automatism and conductivity in the heart. Potassium and magnesium asparaginate normalizes metabolic processes in cardiomyocytes, decreases automatism, inhibits the myocardial conductivity and excitability, decreases the heart rate and contractility. M-cholinoblockers eliminate the suppressing influence of the vagus nerve (bradycardia) on the heart conductive system. β-adrenomimetics stimulate β1-AR of the heart, increase the concentration of Ca2+-ions and cAMP in cardiomyocytes increasing the myocardial excitability and conductivity and eliminating different forms of bradyarrhythmias.

77 Pharmacodynamics (effects) → Indications Anti-arrhythmic (all medicines), local Atrioventricular tachyarrhythmia, anesthetic (Lidocaine) ventricular extrasystolia; local anesthesia (Lidocaine) Anti-anginal, antihypertensive (β-adreno- Angina pectoris, hypertension blockers, calcium antagonists) (fig. 4) Side effects → Contraindications Neurotoxicity, increase of the cardiac Chronic cardiac, renal and hepatic insufficiency symptoms, the BP decrease insufficiency

The pharmacological “face” of anti-arrhythmic medicines Blocker of Medicines Ion canals β 1-adreno- Other effects Na+ Ca2+/K+ receptors Quinidine +++ -/++ Antipyretic, analgesic, local anesthetic, uterotonic Procainamide +++ -/++ Hypotensive, anticholinergic Lidocaine + Local anesthetic Propranolol + +++ Sedative, anti-anginal, hypotensive Metoprolol + +++ Anti-anginal, hypotensive Verapamil + +++/- Potassium and Effective in poisoning by cardiac magnesium The source of K+, Mg2+ glycosides asparaginate

Fig. 4. Effects of calcium canals blockers on the cardiovascular system

INN, (Trade name) Medicinal form, dosage Amiodaron (Cordaron) Tabl. 0.02; sol. for inj. 5% Atenolol Tabl. 0.05

78 Atropine sulphate Sol. 0.1% Dobutamine Sol. for inj. 0.5% Isoprenaline (Isadrine, Novodrine) Tabl. 0.005 Lidocaine (Xycaine) Sol. for inj. 1% Metoprolol (Corvitol) Tabl. 0.1 Potassium and magnesium asparaginate Tabl. 0.35 (Asparkam, Panangin) Procainamide (Novocainamide) Tabl. 0.25; sol. for inj. 10% Propranolol (Anaprilin) Tabl. 0.01; 0.04 Quinidine Tabl. 0.2 Verapamil (Lekoptine, Finoptine) Tabl. 0.04; sol. for inj. 0.25%

Glossary Anti-anginal effect is the removal of the imbalance between the oxygen consumption by myocardium and its supply with blood (removal of the IHD symptoms). Arrhythmia is a dysfunction of the heart rhythm. Cardiomyocyte is the cell of myocardium. Polarization is the state of rest of the cell membrane. Sinoatrial and atrioventricular nodes are drivers of the heart rhythm, a parts of the heart conductive system. Extrasystolia is the extra heart contraction or contraction of any of its parts on the background of general rate.

VII. MEDICINES AFFECTING THE GIT

MEDICINES THAT AFFECT APPETITE

Appetite or feeling of hunger is determined by the activity of centres of hunger and satiation located in the hypothalamus. Stimulation of noradrenaline neurotransmission in the CNS leads to inhibition of the centre of hunger, and stimulation of serotoninergic neurotransmission activates the centre of satiation. Two main disorders of appetite are distinguished such as anorexia and bulimia. Correction of appetite dysfunctions is performed with the help of or anorexigenic (appetite decreasing) and anti-anorectic or anti-anorexigenic (appetite increasing) medicines.

Classification of medicines Anti-anorectic medicines (bitters) Anorectic medicines Wormwood herb Amphetamine sulphate Dandelion root Phepranone Sweet flag rhizome Phenylpropanolamine Collection for appetite Fluoxetine Sibutramine

The mechanism of action While irritating the afferent nerves endings bitters increase in reflex the excitability of the centre of hunger that causes the gastric juice secretion, increasing of appetite and improving of digestion. Amphetamine, phepranone, phenylpropanolamine increase the release of NA and inhibit its re-uptake stimulating the brain cortex and inhibiting the centre of hunger. Fluoxetine inhibits the re-uptake

79 of serotonin that leads to activation of the centre of satiation. Sibutramine inhibits the re-uptake of NA and serotonin and, thus, suppresses the centre of hunger and stimulates the centre of satiation.

Pharmacodynamics (effects) → Indications Anti-anorectic (increase of appetite, Anorexia (neurogenic, in hypoacidic, improvement of digestion) atrophic gastritis, etc.) Anorectic (decrease of appetite, loss of Obesity, bulimia of the different genesis weight) Side effects → Contraindications Addiction (in long-term administration of Hypertension, tachyarrhythmia, the CNS amphetamine, phepranone, excitation, pregnancy phenylpropanolamine), anxiety, insomnia, tachycardia, hypertension (all anti-anorectic medicines) Increase of the gastric juice secretion Hyperacidic states (bitters)

The pharmacological “face” of medicines affecting appetite Medicines Peculiarities Bitters They are medicines of the plant origin that contain glycosides of a bitter . They are taken 15-20 min before meals. Their action reveals only the background of meals Amphetamine (see psychomotor Indirect-acting adrenomimetic; very stimulants) strong psychostimulating, cardio- stimulating, hypertensive effects. It is not used for the course treatment Phepranone Indirect-acting adrenomimetic with more selective anorectic effect, less toxic than amphetamine Phenylpropanolamine Sedative effect Sibutramine It affects simultaneously on the centres of satiation and hunger, has the antidepressant effect

The list of medicines INN, (Trade name) Medicinal form, dosage Amphetamine sulphate (Phenamine) Tabl. 0.01 Collection for appetite Pack 100.0 Dandelion root Pack 100.0 Fluoxetine (Prozak) Tabl. 0.02 Phenylpropanolamine Tabl. 0.025 Phepranone (Amphepranone) Dr. 0.025 Sibutramine Caps. 0.01

80 Sweet flag rhizome Pack 50.0 Wormwood herb Pack 100.0

Glossary Anorexia is the complete loss of appetite. Bulimia is pathologically increased feeling of hunger.

EMETIC AND ANTI-EMETIC MEDICINES These medicines inhibit (anti-emetic) or stimulate (emetic) different parts of the nervous system selectively, responsible for the vomiting: receptors of the gastric mucous membrane, vestibular apparatus, trigger zone of the medulla oblongata.

Classification of medicines Emetic medicines: Anti-emetic medicines central- and reflex*- (M-cholinoblockers*, H1-histaminoblockers**, 5-HT3- acting serotoninoblockers***, D2-dophaminoblockers) Apomorphine h/chl. Scopolamine h/chl.* Ipecacuanha root syrup * ** *** Metoclopramide Haloperidol

The mechanism of action Reflex-acting emetic medicines irritate nerve endings of the gastric mucous membrane, do not affect the CNS; central-acting medicines stimulate the dophamine receptors of the emetic centre trigger zone. Anti-emetic medicines block D2-dophamine, serotonin-5-HT3-receptors of the emetic centre trigger zone; M-ChR and H1-histamine receptors in the CNS.

Pharmacodynamics (effects) → Indications Emetic Acute poisonings; production of the negative conditioned reflex in alcoholism Anti-emetic Vomiting in motion sickness, radiation affection, antitumour therapy, toxicosis in pregnant women Side effects → Contraindications BP decrease, extrapyrami- Extrapyramidal disorders (D2-dophaminoblockers), dal disorders diseases of the heart and the CNS

The pharmacological “face” of anti-emetic medicines Used in Medicines motion Chemo-, radiation therapy of toxicosis sickness tumours Scopolamine h/chl. + Diphenhydramine + + + Tropisetron + Metoclopramide + + Haloperidol +

The list of medicines INN, (Trade name) Medicinal form, dosage Apomorphine h/chl. (Yuprima) Sol. for inj. 1%

81 Diphenhydramine (Dimedrol) Sol. for inj. 1%; tabl. 0.05 Ipecacuanha root syrup Vial Haloperidol (Halopril, Halidor) Tabl. 0.005; sol. for inj. 0.5% Metoclopramide (Cerucal) Tabl. 0.05; sol. for inj. 0.5% Scopolamine h/chl. Sol. for inj. 0.5% Tropisetron (Navoban) Sol. for inj. 0.1%

Glossary Extrapyramidal disorders see neuroleptics (antipsychotics).

ANTI-ULCER MEDICINES

Classification of medicines Antisecretory medicines Antacid and covering Inhibitors of H2-histamine M1-cholino- medicines (monocomponent H+/K+-ATPase receptors blockers blockers and combined*) Omeprazole Famotidine Pirenzepine Aluminium phosphate Almagel* Maalox* Gastroprotectors Antihelicobacter medicines Medicines of plant origin Bismuth subcitrate Metronidazole Gastrophyt Misoprostol Bismuth-containing medicines Plantaglucide

The mechanism of action Inhibitors of H+/K+-ATPase or blockers of ― pump‖ inhibit the activity of the H+/K+-ATPase enzyme and, thus, they block the function of the ―proton pump‖ stopping the hydrogen ions secretion by oxyntic cells of the stomach and it is accompanied by the inhibition of the hydrochloric acid formation there. Blockers of H2-histamine receptors inhibit the secretion of the hydrochloric acid in the stomach by competing inhibition of the histamine interaction with H2-histamine receptors of stomach cells. M1-cholinoblockers block M1-ChR of the gastric mucous membrane selectively and it leads to the inhibition of the hydrochloric acid and pepsinogen secretion by the gastric glands. Antacid medicines chemically react with the hydrochloric acid of the gastric juice and neutralize it. Covering medicines form a film from colloid that protects the sensitive nervous endings of the gastric mucous membrane from the action of irritants and the hydrochloric acid. Bismuth-containing medicines (bismuth subcitrate) as astringent medicines bind the tissue proteins forming albuminates that protect the gastric mucous membrane from aggressive affects (HCl and other substances). Misoprostol (a synthetic prostaglandine analogue) substitutes the natural component of the gastric mucus, replenishes its deficiency and stabilizes the protective barrier of the gastric mucous membrane; improves the microcirculation. Antihelicobacter medicines have the bactericidal effect against Helicobacter pylori. Plantaglucide, Gastrophyt are medicines of the plant origin, which mechanism of action is stipulated by their composition: they stimulate the reparative processes and decrease inflammation in the gastric mucous membrane, normalize the GIT functions.

82 Pharmacodynamics (effects) → Indications Anti-ulcer effect Peptic (stomach and duodenal) ulcer, hyperacidic gastritis (all, except Plantaglucide). Hypoacidic gastritis, peptic ulcer with normal or decreased acidity (Plantaglucide, Gastrophyt) Side effects → Contraindications Dyspepsia, Hepatic, renal functional disorders; pregnancy headache, dizziness The pharmacological “face” of anti-ulcer medicines  of of  H. Medicines Other effects/peculiarities HCl/pepsin secretion** pylori Aluminium It is effective in +* + - phosphate intoxications Almagel Adsorbent, covering, */+ + - choleretic, effects Maalox */+ + - Covering effect Bismuth Antiseptic, astringent effect - + ++ subcitrate Omeprazole ++++/+ - + Cytoprotective Pirenzepine ++/+ - - Spasmolytic effect Famotidine The IIIrd generation +++/+ - - medicine, 10 times more effective than ranitidine Metronidazole -/- - +++ Misoprostol Synthetic prostaglandin ++/+ ++ - analogue. Cytoprotective. intestinal and uterine tone Gastrophyt Consists of 15 plants. Anti- -/- - - inflammatory, choleretic effects * − medicines that do not inhibit secretion, but neutralize the free HCl; ** - mucus and bicarbonates in stomach. The list of medicines INN, (Trade name) Medicinal form, dosage Aluminium phosphate (Phosphalugel) Gel 16.0 Almagel Gel, vial 200 ml Bismuth subcitrate colloidal (De-nol, Ventrisol) Tabl. 0.12 Famotidine (Famosan) Tabl. 0.02 Gastrophyt Pack 100.0 Maalox Susp., vial 250 ml Metronidazole (Clion, Trichopol) Tabl. 0.25; sol. for inj. 0.5% Misoprostol (Saytotek) Tabl. 0.0002 Omeprazole (Omez) Caps. 0.02 Pirenzepine (Gastrocepine) Tabl. 0.025; sol. for inj. 0.5% Plantaglucide Granules 2.0

83 Glossary Anti-ulcer effect is decrease of clinical symptoms of peptic ulcer exacerbation and the ulceration area in the GIT. Helicobacter pylori is a gram-negative microorganism that takes part in the peptic ulcer formation.

HEPATOPROTECTORS These are medicines that increase liver resistance to pathologic affections; they promote the renewal of its functions in different disorders.

Classification of medicines Medicines of the plant Medicines containing Synthetic medicines and animal* origin aminoacids and essential phospholipids* Hepatophyt Flamine Glutargine Antral Liv-52 Silibinine Essential* Lioliv Tyqueol Hepabene Thiotriazoline Syrepar* Ursodesoxycholic acid

The mechanism of action The common elements in the mechanism of the action of hepatoprotectors are their ability to: - intensify the detoxication processes due to the improvement of the hepatocyte monooxygenase systems functioning and the intensification of the conjugation processes; - inhibit the processes of free radical oxidation of hepatocytes (the antioxidant effect); - stabilize the hepatocytes’ membranes, decrease the cytolysis phenomena (the membrane-stabilizing effect); - decrease the hepatocyte inflammation due to the influence on immunological and biosynthetic processes in the hepatic tissue (the anti-inflammatory effect); - normalize the tissue respiration processes (mainly due to the cytochrome system) and oxidative phosphorylation; - improve the energy supply of hepatocytes. Essential phospholipids, besides these effects, provide the restoration of the structure and functions of cellular and sub-cellular membranes and, thus, they eliminate defects in the cell membranes caused by hepatotoxins.

Pharmacodynamics (effects) → Indications Hepatoprotective, antitoxic, antioxidant, Hepatitis, hepatic cirrhosis, membrane-stabilizing, anti-inflammatory chronic cholecystitis, dyskinesia of the biliary tract and the gall bladder Side effects → Contraindications Dyspepsia, discomfort in the epigastric area Acute hepatitis, hepatic coma, chronic renal insufficiency

84 The pharmacological “face” of hepatoprotectors Effects Other Medicines a/i a/o m/s ch/r effects/peculiarities Antral + + + + Analgesic, Lioliv + + + + immunostimulating Thiotriazoline Cardioprotective, + + + + anabolic Tyqueol Prostate-protective, anti- + + + + ulcer Silibinine + + + Hepatophyt It contains 9 plants; + + + + hypoglycemic Liv-52 BAS from 8 plants; appetite,  risk of + + + + cholelithiasis development Essential* Protein synthesis stimulant, hypolipidemic + + + effect, it contains essential phospholipids Glutargine Combination of the + + and arginine; detoxication a/i – anti-inflammatory; a/o – antioxidant; m/s – membrane-stabilizing; ch/r – choleretic effects; BAS – biologically active substances.

The list of medicines

INN, (Trade name) Medicinal form, dosage Antral Tabl. 0.1; 0.2 Essential Caps. 0.3; sol. for inj. 5 ml Flamine Tabl. 0.05 Glutargine Tabl. 0.25; sol. for inj. 4%; 40% Hepabene Caps. Hepatophyt Pack 100.0 Lioliv Pwd. for inj. 0.644 Liv-52 Tabl. Silibinine (Carsil, Legalone, Silibor) Tabl. 0.035; caps. 0.07 Syrepar Sol. for inj. 1% Thiotriazoline Tabl. 0.1; supp. 0.2; oint. 2% Tyqueol Sol. 50 ml; 100 ml Ursodesoxycholic acid (Ursofalk) Tabl. 0.1

85 Glossary Hepatocyte is a cell of the liver. Dyskinesia is the motility disorder of the smooth muscle organ (biliary tract, etc.). Choleretic (bile-expelling) effect is increase of bile production and release. Cytochromes are enzymes that contain iron and have the function of the electrons and hydrogen ions transport, i.e. they take part in the tissue respiration.

LAXATIVE MEDICINES Laxatives are medicines that increase the motor function of the intestine or make the intestinal contents soft fastening the defecation.

Classification of medicines Medicines stimulating intestinal Medicines stimulating intestinal chemoreceptors mechanoreceptors Plant origin: Medicines swelling in the intestine: Glaxena Regulax Laminaria saccharina Ramnus cathartica bark Castor oil Synthetic: Salt laxatives: Sodium picosulphate Magnesium sulphate Medicines making intestinal contents soft Vaseline oil The mechanism of action Intensification of the GIT peristalsis by the stimulation of chemo- or mechanic receptors of the intestine or softening of feces with relieve of their movement along the intestine. Pharmacodynamics (effects) → Indications Laxative effect Constipation, preparation to operations, instrumental examination of the GIT; food poisonings; regulation of stool in hemorrhoid and proctitis Side effects → Contraindications Increase of the GIT motility and Intestinal obstruction, spastic colitis. peristalsis (colic-like pain). Disorder of Simultaneous intake with medicines that drug and food absorption from the GIT are absorbed from the GIT

When magnesium sulphate is administered parenterally, it inhibits the CNS and depending on the dose has sedative, hypnotic, general anesthetic effects. The medicine has also spasmolytic, hypotensive, and in high doses – anticonvulsant effect. Laxatives are not recommended to prescribe for a long period of time to avoid disorders of the intestine’s functions (development of diarrhea with metabolic disorders, decrease of the intestinal enzymes function, digestion disorders, the large intestine atony, water-electrolyte balance disorder, etc.). The pharmacological “face” of laxative medicines The onset Peculiarities of Medicines of action, h pharmacodynamics/application Glaxena 8-10 Chronic constipation Ramnus cathartica bark

86 Castor oil Uterotonic effect, acute constipation, 2-6 radiography of the GIT organs, labour induction Sodium picosulphate Chronic constipation, urographics, recto- 6-10 and coproscopy Laminaria saccharina 8-10 Chronic constipation Magnesium sulphate Acute constipation, poisonings; 3-5 choleretic effect Vaseline oil Chronic constipation, poisonings by 1 liposoluble poisons, anal cracks, hemorrhoid

The list of medicines INN, (Trade name) Medicinal form, dosage Castor oil Vial 50.0; caps. 1.0 Glaxena Tabl. 0.0135 Laminaria saccharina Syrup, pwd. Magnesium sulphate (Cormag- Pwd. 50.0 nesine) Ramnus cathartica bark Pack 100.0 Regulax Sol.; blocks Sodium picosulphate (Guttalax) Dr. 0.005; sol. 0.75% Vaseline oil Vial 50 ml

Glossary Hemorrhoid is the pathological change of the straight intestine vessels with rectal bleedings, pain and prolapse of hemorrhoids. Constipation is a delayed, difficult or incomplete emptying of the intestine. Proctitis is inflammation of the rectal mucous membrane.

MEDICINES OF DIGESTION ENZYMES. ANTI-ENZYMATIC MEDICINES

Pancreas is an important digestion organ. Pancreatic enzymes (lipase, amylase and proteases) split the food components. In pancreatic diseases medicines stimulating or substituting the exocrine function of the pancreas (enzymatic medicines) and medicines inhibiting the activity of its proteolytic enzymes (anti-enzymatic medicines) are used.

Classification of medicines Enzymatic medicines Anti- Pancreatic Pancreatic Pancreatic enzymes+bile+ enzymatic enzymes enzymes+bile+ aminoacids+ HCl medicines hemicellulase Pancreatine Festal Panzynorm-forte Aprotinine Mezym-forte Enzystal

87 The mechanism of action Enzymatic medicines split proteins (protease), lipids (lipase) and carbohydrates (amylase). Bile acids that are contained in enzymatic medicines emulsify lipids, increase the activity of lipase and improve absorption of lipids and liposoluble . Aminoacids stimulate secretion of the gastric juice, and hemicellulase promotes splitting of plant cellulose in the small intestine lumen, microflora normalization, decrease of formation. Anti-enzymatic medicines inhibit the activity of trypsin, chemotrypsin, callicreine, plasmin and other proteases forming inactive complexes with these enzymes; inhibit and suppress kinins formation.

Pharmacodynamics (effects) → Indications Deficiency substitution of pancreatic Substitution therapy in pancreatic enzymes, normalization of digestion insufficiency (chronic pancreatitis, (enzymatic medicines) enterocolitis) Stoppage of self-digestion of the Prevention of autolysis of the pancreas in pancreas, removal of hemorrhages and acute pancreatitis; after operations on edema there (anti-enzymatic medicines) organs that are close to the pancreas Side effects → Contraindications Allergy to pork or beef protein. Diarrhea Individual intolerance of pork or beef or constipation (when using high doses). protein. Intestinal obstruction. Acute The syndrome of ―abrupt pancreatitis (first 7-10 days) and discontinuation‖ in the prolonged exacerbation of chronic pancreatitis (first application (enzymatic medicines) 3-5 days) Decrease of the secretion of pancreatic Insufficient pancreatic function digestive enzymes (anti-enzymatic medicines)

The pharmacological “face” of enzymatic medicines Effect  bile intestinal  pain in Medicines Composition  me- secre- motility chronic teorism tion regulation pancreatitis Pancreatine Extract of the cattle pancreas containing - - - + protease, amylase, lipase Mezym- Extract of the pork forte pancreas containing - - - + pancreatine Festal Pancreatine, bile components, + + + - hemicellullase Enzystal Pancreatine, bile components, + + + - hemicellullase

88 Panzynorm- Pancreatine, bile forte components, + + - - aminoacids, HCl

The list of medicines INN, (Trade name) Medicinal form, dosage Aprotinine (Gordox) Pwd. for inj. 12 U/vial Enzystal Tabl. Festal Dr. Mezym-forte Dr. Panzynorm-forte Dr. Pancreatine Tabl. 0.25

Glossary Autolysis is a self-digestion of the pancreas. Fibrinolysis is a process of dissolution of a fibrin blood clot.

VIII. MEDICINES AFFECTING THE RENAL FUNCTION

DIURETIC MEDICINES (DIURETICS)

Diuretics are medicines that increase diuresis, excrete the excessive amount of liquid from an organism and remove edemas. There is a retention of liquid in the organism with formation of edamas in renal diseases (nephritis, nephrosis, pyelonephritis), urinary tract diseases (pyelitis, cystitis), cardiovascular system diseases (cardiac insufficiency, decompensated heart diseases, myocardial infarction, cardiosclerosis), hepatic pathology (cirrhosis, etc.). The main role in the development of edemas of any origin belongs to the primary retention of sodium in the organism. The increase of its concentration in blood and in the interstitial liquid leads to the increase of the osmotic pressure and the secondary retention of water in tissues. That is why diuretics are prescribed simultaneously with treating the basic diseases (heart, kidneys, liver, etc.) to accelerate the sodium and water elimination. Their action is mainly directed to the renal function, in particular, to the processes of the primary urine filtration in glomeruli, reabsorption – inverse absorption of water and diluted substances - in tubules, secretion – excretion of substances by the tubular epithelium. The process of the urine formation is under neurohormonal control. Thus, adrenal hormones, especially aldosterone, affect the elimination of sodium and chlorine. A sodium-uretic factor, which causes the marked sodium-uresis (elimination) and increases diuresis, was isolated from cardiomyocytes of the atria and liver. The renal function is also regulated by prostaglandins causing the increase of the blood flow in the kidneys and, correspondingly, the intensification of filtration process.

Classification of medicines There are several classifications of diuretics. Firstly, diuretics are divided by the impact of action: those intensifying mainly the water diuresis (osmotic); those intensifying the elimination from the

89 organism mainly Na+, K+, Cl-: loop and diuretics (they are called saluretics); those intensifying Na+ elimination and blocking K+ elimination (potassium-saving or potassium-sparing diuretics). Secondly, they are divided by the strength of the diuretic effect (mainly by their ability to increase Na+ excretion with urine) into strong-acting diuretics: loop diuretics (inhibit Na+ reabsorption by 10-25%); medium- acting diuretics (inhibit sodium reabsorption by 5-10%): thiazide and thiazide-like, osmotic diuretics; weak-acting diuretics: potassium-saving, plant origin diuretics, carboanhydrase inhibitors, xanthine derivatives. Thirdly, by the onset and duration of action diuretics are divided into fast- (30-40 min) and short- (2-4 h) acting: , urea, triamteren, ethacrynic acid, mannitol; ones with medium onset (2-4 h) and duration (8-14 h) of action: theobromine, aminophylline, acetazolamide, amyloride, hydrochlorthiazide, clopamide; slow- (2-5 days) and long- (2-3 days) acting ones: spironolactone. By the influence on the acid-base balance in blood diuretics are divided into those causing the marked metabolic acidosis: acetazolamide; those causing metabolic acidosis: amyloride, triamteren, spironolactone; and those causing moderate alkalosis: chlortalidone, furosemide, etc. Diuretics are also classified by localization of their action in different parts of the nephron.

Table 4. Diuretics acting on Proximal section of convoluted tubules Ascending section of Distal section of convoluted including other nephron the Henle’s loop tubules sections* Carboanhydrase Thiazide and thiazide-like* inhibitors and osmotic Loop diuretics diuretics diuretics * Acetazolamide Furosemide Hydrochlorthiazide Mannitol* Ethacrynic acid Chlortalidone Clopamide* Urea* Indapamide* Collecting ducts area and the distal tubular Nephron’s glomeruli Glomeruli and tubules section* Potassium-sparing Plant origin: monomedicines Xanthines and combined* ones Spironolactone Aminophylline Nephrophyt* Triamteren Theobromine Orthosiphone leaf Amyloride* Bearberry leaf Triampur Lespenephril compositum*(comb.) Horse-tail herb

The mechanism of action The mechanism of the acetazolamide’s action is connected with the inhibition of the carboanhydrase enzyme activity that activates the carbonic acid

90 formation process in cells of the tubular epithelium and dissociation of the carbonic + - + acid on H and HCO 3 ions. It inhibits H ions coming into urine in exchange for Na+ ions. The metabolic reabsorption of sodium and hydrogen ions is slowing down, and NaHCO3 (sodium hydrocarbonate) of the primary urine is intensively excreting by the kidneys. With the intensive excretion of sodium hydrocarbonate by urine the latter gets the alkaline properties, and blood (because of the H+ ions retention by the kidneys) gets the acidic properties (acidosis). The decrease of the IOP and ICP by carboanhydrase inhibitors is connected with block of the vascular plexus carboanhydrase in the brain’s ventricles (the production of the cerebrospinal fluid is decreased) and in the ciliary body (the production of the intraocular fluid is decreased). Carboanhydrase inhibitors decrease the content of sodium and water in the brain’s neurons and it leads to inhibition of their excitability. As a result, the anti-epileptic effect of diuretics from this group develops. Osmotic diuretics do not influence on the electrolyte reabsorption. When introducing intravenously they increase the osmotic pressure in the vascular bed. Consequently, the increased osmotic pressure, which decreases reabsorption of sodium and water, appears in the primary urine since water is retained by osmotically active substances. Medicines act along the whole tubules. Excretion of sodium using osmotic diuretics occurs slower than excretion of water, and excretion of potassium does not change. Owing to the blockade of sulphohydryl groups of enzymes loop diuretics inhibit the energy forming processes (for example, oxidative phosphorilation) and it leads to decrease of reabsorption of sodium, magnesium and partially potassium ions from urine to cells, the latter one reduces water reabsorption. They promote the excretion of Na +, K+, Cl-, Ca2+, Mg2+ salts from the organism and inhibit carboanhydrase in high doses. Thiazide and thiazide-like diuretics inhibit the activity of Na+, K+-ATP-ase, succinate dihydrogenase and bind carboanhydrase. Consequently, the supply of the sodium pump by the energy and Na+, Cl- reabsorption reduces. It stipulates the increase of diuresis and sodium elimination. The mechanism of action of potassium-sparing diuretics is not the same. Spironolactone has a steroid structure, which is similar to the aldosterone’s structure, being its competitive antagonist. Promoting the Na+ transfer through the cell membranes the medicine intensifies the sodium ions excretion from the organism and inhibits the elimination of K+ and Mg2+. Triamteren and amyloride are non-competitive antagonists of aldosterone, cause a direct blocking action on the Na+ transport through the sodium canals of distal tubules of the kidneys. That is why they decrease the Na+ reabsorption and the K+ secretion, increase diuresis. Triampur compositum contains triamteren and hydrochlorthiazide. The main mechanism of xanthine diuretics action is intensification of the renal blood flow in the kidneys and filtration intensification in the glomeruli. These medicines also decrease the processes of the + - Na , Cl , H2O tubular reabsorption. The mechanism of the diuretic action of plant diuretics has not been studied enough. Volatile oils, organic acids, glycosides, , containing in plants are considered to intensify the blood circulation in the kidneys, increase their filtration ability and partially affect the tubular reabsorption.

91 Pharmacodynamics (effects) → Indications The main effect of diuretics is diuretic Pulmonary edema, edemas in diseases of heart, vessels, kidneys and liver Loop, thiazide and thiazide-like The complex therapy of hypertension, diuretics have the hypotensive effect hypertensive crisis Spironolactone decreases the cardiac Edema in heart failure post-load, loop diuretics decrease the pre-load on the heart Osmotic and loop diuretics, Brain edema, glaucoma carboanhydrase inhibitors cause the dehydrative effect, decreasing the IOP and ICP Acetazolamide has the anti-epileptic Epilepsy (petit-mal) effect Medicines of the plant origin have also Prevention of edemas in cardio the hypoazotemic (Lespenephril, vascular, renal and hepatic diseases Nephrophyt), anti-inflammatory, antimicrobial, spasmolytic, choleretic effects; some of them excrete urinary concrements (Cowberry leaf, Nephrophyt) Side effects → Contraindications Hypokalemia (carboanhydrase inhibitors, Acidosis, uremia, hepatic cirrhosis, thiazide, loop diuretics); hyperkalemia renal diseases, Addison’s disease (potassium-sparing); hyposodemia, (carboanhydrase inhibitors); hypomagnemia (loop diuretics, hypomagnemia, hypokalemia, potassium-sparing, thiazide diuretics); hyposodemia, dehydration, severe hypercalcemia (thiazide and thiazide- forms of diabetes (loop, thiazide like); hypochloremic alkalosis (loop, diuretics) thiazide and thiazide-like diuretics); hyperchloremic metabolic acidosis (carboanhydrase inhibitors, potassium- sparing); hyperglycemia, hyperuricemia (loop, thiazide and thiazid-like, potassium-sparing diuretics)

The pharmacological”face” of diuretics

Effect Cause

Medicines

(h)

start

strength acidosis

duration duration alkalosis Furosemide ++++ 5 min i/v; 30-40 4-8 + min per os

92 Urea +++ 15-20 min 8 Triamteren + 2-4 h 8 Mannitol ++++ 20 min 8 Theobromine + 2-4 h 8-14 Acetazolamide + 2-4 h 8-14 + Amyloride + 2 h 24 + Spironolactone + 2-4 h 24-48 + Hydrochlorthiazide ++ 1-2 h 10-12 + Indapamide ++ 2 h 12-24 + Clopamide ++ 2-3 h 15-16 + Nephrophyt + It contains 12 plants Chlortalidone ++ 2-4 h 24-48 +

The list of medicines INN, (Trade name) Medicinal form, dosage Amyloride Tabl. 0.005 Aminophylline (Euphylline) Tabl. 0.15; sol. for inj. 2% Acetazolamide (Diacarb, Fonurit) Tabl. 0.25 Bearberry leaf Pack 100.0 Chlortalidone (Hygrotone) Tabl. 0.05 Clopamide (Brinaldix) Tabl. 0.2 Ethacrynic acid (Uregit) Tabl. 0.05 Furosemide (Lazix) Tabl. 0.04; sol. for inj. 1% Horse-tail herb Pack 100.0 Hydrochlorthiazide (Hypothiazide) Tabl. 0.025 Indapamide (Ariphon) Tabl. 0.0025 Lespenephril Sol. 120 ml Mannitol (Mannit) Sol. for inj. 20% Nephrophyt Pack 100.0 Orthosiphone leaf Pack 100.0 Spironolactone (Verospirone) Tabl. 0.025 Theobromine Tabl. 0.25 Triamteren (Pterofen) Caps. 0,05 Triampur compositum Tabl. Urea Pwd. for inj. 30.0; 60.0

Glossary Acidosis is the shift of the blood pH to the acid side. Alkalosis is the shift of the blood pH to the alkaline side. IOP (intraocular pressure) is the pressure of the intraocular fluid in the eye’s cavity. Dehydration is the decrease of the water content in tissues.

93 ANTIGOUTY MEDICINES Gout is the disease of metabolism with localization of the inflammatory site and deposition of uric acid salts crystals (urates) in joints that is accompanied by their inflammation and pain attacks. Medicines that decrease the uric acid synthesis (uricodepressive) or increase its elimination from the organism (uricosuric) are used for treatment gout.

Classification of medicines Uricodepressive ones Uricosuric ones Mixed acting ones Allopurinol Sulphinpyrasone Allomarone (combined) Benzobromarone

The mechanism of action Allopurinol inhibits the xanthinoxidase enzyme, disturbs the hypoxanthine transformation into xanthine and then into the uric acid. Uricosuric medicines increase the uric acid excretion decreasing the urates reabsorption and increasing their secretion in the kidneys. Allomarone alters the uric acid synthesis, inhibits its reabsorption, promotes the excretion of the uric acid.

Pharmacodynamics (effects) → Indications Antigouty effect Gout, hyperuricemia Side effects → Contraindications Dyspepsia, hyperthermia, eosinophilia, Peptic ulcer, diseases of blood, liver, leukopenia kidneys; pregnancy, lactation

The pharmacological “face” of antigouty medicines Medicines Peculiarities Allopurinol It is also used in nephrolithiasis, arthritis, Sulphinpyrasone It has also the anti-aggregant effect Benzobromarone It has the analgesic effect and is also used in arthritis with hyperuricemia, psoriasis Colchicine Anti-inflammatory, analgesic, effect. It is also used in nephrolithiasis, chondrocalcinosis, amiloidosis, Behchet`s disease Allomarone It contains allopurinol and benzobromarone

The list of medicines INN, (Trade name) Medicinal form, dosage Allomarone Tabl. Allopurinol (Alupol, Milurit) Tabl. 0.1 Benzobromarone (Desuric, Hypuric) Tabl. 0.1 Colchicine Tabl. 0.1 Sulphinpyrasone (Anturan) Tabl. 0.1

Glossary Hyperuricemia is the increase of the uric acid level in blood. Nephrolithiasis is the presence of concrements in the urinary tract.

94 IX. MEDICINES AFFECTING THE BLOOD COAGULATION SYSTEM AND FIBRINOLYSIS

Imbalance between the functional blood coagulation and anticoagulation (fibrinolysis) systems leads to development of thrombosis or hemorrhage (bleeding).

Plasma and thrombocyte factors of blood coagulation as an object of drug affection The natural state (fluidity and coagulation) of blood is provided by the factors of the vascular wall, proteins (proconvertin, prothrombin, fibrinogen), which are synthesized in the liver with the participation of and blood cells – thrombocytes. The mechanism of blood coagulation is performed at three (I-III) stages (phases): while damaging vascular wall the formation of the active thromboplastin (I), which promotes conversion of prothrombin to (II) that converts fibrinogen to fibrin-monomer, which, in its turn, coverts into fibrin-polymer as a result of clot retraction (III). Thus, bleeding is stopped. Thrombocyte aggregation is regulated by the thromboxane-prostacycline system. Thromboxane A2 is synthesized in thrombocytes, stimulates vasoconstriction and thrombocyte aggregation. Prostacycline is formed in the endothelium of the vascular wall, inhibits adhesion of thrombocytes to the vascular wall and causes . Any kind of disorders of blood coagulation (hemorrhagic and thromboembolic states) requires pharmacological correction. For this purpose anticoagulative () medicines, which decrease the process of blood coagulation, or antihemorrhagic (hemostatic) medicines, that intensify the process of blood coagulation are used. These two groups of medicines influence in the opposite directions on three processes that support blood homeostasis: thrombocyte aggregation, fibrin thrombus formation and their lysis.

MEDICINES DECREASING BLOOD COAGULATION (ANTITHROMBOTIC)

Classification of medicines Direct-acting anticoagulants Indirect-acting anticoagulants Resorptive-acting ones Local-acting ones Acenocumarol Heparin** Heparin ointment Fenindion Calcium nadroparin* *– low molecular heparins; ** – high molecular heparins

Fibrinolytics Antiaggregants Fibrinolysine Dipyridamol Urokinase Ticlopidine Streptokinase Acetylsalicylic acid

The mechanism of action Direct-acting anticoagulants have a powerful negative charge, which promotes the formation of the complex with positively charged coagulation proteins. As a result, procoagulating properties of coagulation proteins are inhibited. Indirect- acting anticoagulants have no influence on coagulation factors directly in the blood.

95 They interfere the biosynthesis of coagulation proteins (proconvertin and prothrombin) in the liver as a result of antagonism with vitamin K. Fibrinolytics (fibrinolysis activators) transform profibrinolysine (plasminogen) into its active form - fibrinolysine (plasmin), decrease the level of fibrinogen in the blood plasma, inhibit aggregation of thrombocytes and the activity of natural blood procoagulants, i.e. they activate the fibrinolytic system (fibrinolysis). Antiaggregants inhibit the synthesis of thromboxane A2 suppressing thromboxane-synthase and cyclooxygenase enzymes.

Pharmacodynamics (effects) → Indications Direct-acting anticoagulants (inhibition of blood Myocardial infarction, direct blood coagulation at all phases ) transfusion, surgery on the heart or vessels. Prophylaxis and treatment of embolism and vascular thrombosis Fibrinolysis activation, improvement of Prophylaxis of thrombosis after coronary blood rheological properties vessels shunting and prosthetics of the heart valves Antiaggregant (inhibition of adhesion Thrombophlebitis, trophic ulcers of the and aggregation of thrombocytes and shin, hemorrhoids, subcutaneous erythrocytes, normalization of the blood hematomas, hypercoagulation syndrome rheological properties, improvement of microcirculation of the brain, myocardium, retina, etc.) Hypolipidemic (decrease of the lipid Prophylaxis and treatment of level in blood) atherosclerosis Coronarodilating (improvement of Myocardial infarction, stable angina of blood stream in the myocardium) tension Immunosuppressive Direct blood transfusion, surgery on the heart or vessels, rheumatism, bronchial asthma, glomerulonephritis, hemolytic anemia, renal transplantation, endocarditis

Indirect-acting anticoagulants Anticoagulant Prophylaxis and treatment of venous and arterial thrombosis, thrombophlebitis, coronary insufficiency, obliterating endarteritis, hypercoagulation syndrome Hypolipidemic Prophylaxis and treatment of atherosclerosis Fibrinolytics Fibrinolytic (dissolution of fibrin Venous and arterial thrombosis, acute filaments and recent (up to 3 days) myocardial infarction, pulmonary thrombi) embolism

96 Antiaggregants Antiaggregant Prophylaxis and treatment of the hypercoagulation syndrome, chronic coronary insufficiency. Prophylaxis of ischemic stroke and encephalopathies Side effects → Contraindications Bleedings, thrombocytopenia Low blood coagulability, increased permeability of vessels, peptic ulcer, tuberculosis

The pharmacological “face” of anticoagulants and antiaggregants Medicines Route of Onset of effect Duration of administration effect Heparin i/v 5 min 2-6 h i/m 15-30 min 2-8 h s/c 30-40 min 4-12 h Nadroparin* s/c 3-4 h up to 6 h Acenocumarol per os 24-48 h 2-4 days Fenindion per os 10-24 h 24-72 h Dipyridamol** per os, i/v Ticlopidine** per os 1-2 days 8-10 days Acetylsalicylic acid per os 20-30 min up to 7 days * - nadroparin is less toxic than heparin; ** - dipyridamol`s activity is similar to aspirin, and ticlopidine is more active than aspirin.

The pharmacological “face” of fibrinolytics Medicines The sources of Affection on the Antigenic obtaining thrombus properties Fibrinolysine Donor’s blood direct outside High Urokinase Human kidneys cells indirect inside and Practically culture outside absent Streptokinase Hemolytic High culture

The list of medicines INN, (Trade name) Medicinal form, dosage Acenocumarol (Sincumar) Tabl. 0.02 Acetylsalicylic acid (Aspirin) Tabl. 0.3 Dipyridamol (Curantil) Tabl. 0.0025; sol. for inj. 0.5% Fenindion (Fenilin) Tabl. 0.03 Fibrinolysine (Plasmin) Pwd. for inj. 20000 U Heparin (Vetren) Sol. for inj. 1000 U/ml Heparin ointment Oint. 100 U/g Nadroparin calcium (Fraxiparin ) Sol. for inj. 9500 U/ml

97 Streptokinase (Streptolyase) Pwd. for inj. 100000 U Ticlopidine (Ticlid) Tabl. 0.25 Urokinase Pwd. for inj. 100000 U

Glossary Hematoma is a limited accumulation of blood in tissues. Hemocoagulation is coagulation of blood. Hemophilia is inherited insufficiency of the blood coagulation factors, it is an increased bleeding. Hypercoagulation syndrome is pathological increase of the blood coagulation ability and rate. MI (myocardial infarction) is necrosis of the myocardium part. Coronary insufficiency is insufficient supply of the myocardium with blood. Stenocardia (angina) of tension is attacks of retrosternal pain in ischemic heart because of the physical loadings. Thrombophlebitis is the inflammation of a vein with the formation of thrombi there. Thrombocytopenia is the decreased amount of thrombocytes in blood. Thromboembolism is embolism (obstruction) of a vessel by the torn thrombus. Trophic ulcer is defects of the skin or mucous membrane appeared as a result of the blood supply disorder or innervation of tissues disorder with a weak tendency to heal and a tendency of recurrences. Shunting is restoration of the blood supply when the vessel’s site is excluded from the blood circulation.

MEDICINES INCREASING BLOOD COAGULATION (HEMOSTATICS, ANTIHEMORRHAGIC MEDICINES)

Medicines that increase blood coagulation promote stopping bleedings when they are used locally or as a result of the resorptive action.

Classification of medicines Hemostatics Coagulants of the agents Resorptive- Local-acting synthetic, animal, plant (inhibitors of acting origin fibrinolysis) Aminocapronic Fibrinogen Thrombin acid Calcium Hemostatic Gelatin medical chloride sponge Water pepper herb Menadion Nettle herb

The mechanism of action Antifibrinolytic agents inhibit the action of plasminogen and the action of plasmin; suppress the kinins’ system and the activity of fibrinolysis. Hemostatics are natural components of the blood coagulation system. Coagulants of the synthetic, animal and plant origin decrease permeability of the vascular wall, increase the blood viscosity, slow the blood flow, make conditions for forming thrombi.

98 Pharmacodynamics (effects) → Indications Inhibitors of fibrinolysis: bleedings caused by the increased fibrinolysis, thrombocytopenia, including ones caused by peptic and duodenal ulcer, postnatal bleedings Hemostatic effect: Hemostatics: bleedings in surgery, , stoppage or decrease of traumatology caused by deficiency of blood bleedings coagulation system factors: capillary, from parenchymal organs, local bleedings (nasal, extraction of teeth, etc.) Coagulants of synthetic, animal and plant origin: hemorrhagic diathesis, metrorrhagia, nasal, renal, intestinal bleedings Side effects → Contraindications Increase of blood Predisposition to thrombosis, thromboembolism coagulation

The pharmacological “face” of medicines increasing the blood coagulation Medicines The route of Other effects / peculiarities administration Aminocapronic acid per os, i/v Anti-inflammatory, anti-allergic Fibrinogen i/v, locally It is a component of the blood Calcium chloride per os, i/v coagulation system Thrombin locally Menadion per os, i/m, i/v A synthetic water soluble vitamin K analogue Hemostatic sponge locally A mixture of CaCl2 and thrombin on the solid carrier Carbazochrome locally, s/c, i/v A synthetic solid Nettle herb per os Anti-inflammatory, capillary- stabilizing

The list of medicines INN, (Trade name) Medicinal form, dosage Aminocapronic acid (Amicar) Sol. for inj. 5%; tabl. 0.5 Calcium chloride Sol. for inj. 10%; sol. 5% Carbazochrome (Adroxon) Sol. for inj. 0.025% Fibrinogen Pwd for inj. 0.8 Gelatin medical Sol. 10% Hemostatic sponge Plates 10x10 Menadion (Vicasol) Sol. for inj. 1% Nettle herb Pack 100.0 Thrombin Pwd. for inj. 10 ml Water pepper herb Extract

99 Glossary Hemorrhagic diathesis is predisposition to bleedings. Plasmin is an enzyme that destroys clots of blood and turn fibrin to soluble elements. Fibrinogen is a blood plasma protein that transforms to fibrin. Fibrinolysis and fibrinolytic effect is the process of dissolution a fibrin clot as a result of enzymatic reactions.

X. MEDICINES AFFECTING BLOOD FORMATION (HEMOPOIESIS)

CORRECTORS OF ERYTHROPOIESIS

Disorders of erythropoiesis can be caused by decrease of the amount of erythrocytes and hemoglobin (anaemias) or acute increase of the amount of inferior erythrocytes in blood (erythremia). The main types of anaemias are iron deficiency, B12- deficiency, and folic acid deficiency, hypoplastic and hemolytic anaemia.

Classification of medicines Erythropoiesis stimulants Erythropoiesis Iron-containing medicines Vitamins Erythropoietins inhibitors for enteral and parenteral administration Iron fumarate B12, B6, Human Sodium phosphate Jectofer B2, C, erythropoietins solution labeled by Ferroplex Bc, E (α, β, ώ) phosphorus-32 Iron sulphate Iron saccharate Iron chloride Iron hydroxide polymaltose complex

Erythropoiesis stimulants (antianaemic) Iron-containing medicines

The mechanism of action Iron-containing medicines are donors of an iron ion and stimulate the synthesis of hemoglobin.

Pharmacodynamics (effects) → Indications Increase of the hemoglobin amount in Prevention and treatment of iron erythrocytes, improvement of the deficiency (hypochromic) anaemias tissues oxygenation Side effects → Contraindications Ulceration of the GIT, constipation, Diseases of the GIT, anaemias that are not diarrhea, pain in the epigastric area, connected with the deficiency of iron in intestinal colics the organism

100 Vitamins

The mechanism of action Vitamin-containing medicines promote the synthesis of the DNA; intensify the cells’ division and the formation of erythrocytes. Pharmacodynamics (effects) → Indications Stimulation of erythropoiesis Anaemias (especially hyperchromic) Side effects → Contraindications Dyspepsia, tachycardia Diseases of the GIT, tachycardia

Erythropoietins Erythropoietin is the glycopeptide hormone produced by kidneys as a response for hypoxia of different genesis (bleedings, hypochromic and hyperchromic anaemias, the blood circulation disorders) and its role is the erythropoiesis correction. The higher level of the renal hypoxia is, the more erythropoietin is produced. Nowadays with the help of the genetic engineering human erythropoietins α, β, ώ have been obtained.

The mechanism of action Stimulation of proliferation and differentiation of cells of the red bone marrow because of affection the specific erythropoietin’s receptors.

Pharmacodynamics (effects) → Indications Increase of erythrocytes Anaemias caused by the chronic renal insufficiency, and reticulocytes number, HIV- , after usage of cytostatics, in preterm the amount of hemoglobin born infants, hypo- and aplastic anaemias Side effects → Contraindications Increase of BP Hypertension

The pharmacological “face” of iron-containing medicines Medicines The route of The frequency of Composition administration administration Iron fumarate per os 3-4 times a day Iron (II) fumarate Jectofer i/m once/1-2 days Iron (II) in the complex with sorbite and citric acid in dextrane water solution Iron sulphate per os 3-4 times a day Iron (II) sulphate Iron saccharate i/v once/several days Iron (III) saccharate Iron chloride per os 3-4 times a day Iron (II) chloride Iron hydroxide i/m individually Iron (III) hydroxide polymaltose polymaltose complex complex Ferroplex per os 3 times a day Iron (II) sulphate, ascorbic acid II, III – the iron valency.

101 The list of medicines INN, (Trade name) Medicinal form, dosage Ascorbic acid (Vitamin C) Sol. for inj. 5%; tabl. 0.1 Cyanocobalamine (Vitamin B12) Sol for inj. 0.05; 0.1% Jectofer (Ectofer) Sol. for inj. 2ml Iron saccharate (Ferum Lek) Sol. for inj. 2% Iron sulphate (Ferro-gradumet) Tabl. 0.3 Iron fumarate (Ferronate) Caps. 0.35 Iron chloride (Hemofer) Sol. for inj.15.7% Iron hydroxide polymaltose complex (Maltofer) Sol. for inj. 5%; tabl. 0.1 Pirydoxine (Vitamin B6) Sol. for inj. 5%; tabl. 0.01 Riboflavin (Vitamin B2) Tabl. 0.00001 Tocoferol acetate (Vitamin E) Sol. for inj. 5% Ferroplex Tabl. Folic acid Tabl. 0.001 Human erythropoietin (Epomax) Pwd. for inj. 1000; 5000 U

Erythropoiesis inhibitors The mechanism of action Medicines suppress the erythrocytic part of the bone marrow. Pharmacodynamics (effects) → Indications Decrease of the erythrocytes amount Erythremia in blood Side effects → Contraindications Anaemia Erythropenia, HIV-infection The list of medicines INN, (Trade name) Medicinal form, dosage Sodium phosphate solution labeled by phosphorus -32 Sol. for inj.

Glossary B12-deficiency and folic acid deficiency anaemia is anaemia caused by the lack of vitamin B12 and folic acid and it leads to the disorder of the DNA synthesis and disorder of erythropoiesis. Hypoplastic anaemia is a progressive aregeneratory anaemia caused by the dysfunction of the red bone marrow. Hypochromic anaemia is a common name of anaemias characterized by the low colour index of blood. Iron deficiency anaemia is a wide-spread disease of blood characterized by the decreased amount of iron in the organism, in particular in the hemoglobin. Reticulocytes are young erythrocytes. Erythremia is an increased amount of immatured, inferior erythrocytes in blood because of their increased production by the red bone marrow. Erythropenia is the decreased amount of erythrocytes in blood. Erythropoiesis is the process of erythrocytes formation and maturation.

CORRECTORS OF LEUKOPOIESIS Disorders of leukopoiesis are revealed both by deficient production of leukocytes and decrease of their amount in blood (leukopenia, agranulocytosis) and by an increased production of inferior leukocytes (leukosis, leukemia).

102 In the first case leukopoiesis stimulants and colony-stimulating factors that accelerate the formation of leukocytes in the bone marrow are used, in the second case leukopoiesis inhibitors are needed.

Classification of medicines Leukopoiesis stimulants including Leukopoiesis inhibitors colony-stimulating factors (CSF) Lenograstim Methyl-oxymethyluracil Busulfan Molgramostim Sodium nucleospermate Mercaptopurine Ethyl-carboxyphenyl-thiazolidine-acetate

The mechanism of action Leukopoiesis stimulants bind to specific receptors of myeloid cell-precursors of the neutrophilic group, which are necessary for the matured leukocytes formation. It leads to increase of the matured leukocytes synthesis. Leukopoiesis inhibitors suppress the formation of leukocytes.

Pharmacodynamics (effects) → Indications Leukopoiesis stimulants: the Leukopenia including those caused by the increase of the matured leukocytes therapy with antitumour medicines, amount in blood radiation sickness, HIV-infection Leukopoiesis inhibitors: decrease of Leukemias, lymphogranulomatosis the leukocytes amount in blood Side effects → Contraindications Leukopoiesis stimulants: dyspepsia Diseases of the GIT Leukopoiesis inhibitors: inhibition Leukopenia, anaemia, thrombocytopenia, of hemopoiesis, dysfunction of liver diseases of liver and kidneys and kidneys Teratogenecity and embryotoxicity Pregnancy, lactation

The pharmacological “face” of leukopoiesis stimulants Medicines The peculiarities of Other effects Sources of obtaining the influence on leukopoiesis Leno- Regulates the  the antibacterial Recombinant human grastim production and activity of leukocytes granulocytic CSF maturation of neutrophiles Molgra-  the production of Immune-stimulating -//- mostim neutrophiles, (increases the monocytes, phagocytosis) eosinophiles, macrophages Methyl-  erythropoiesis, anti- Synthetic oxy- inflammatory, methyl- reparative, anabolic uracil

103 Sodium Increases the Stimulates the The mixture of nucleo- production of metabolic processes polyhydrates of Na spermate neutrophiles, salts of DNA and lymphocytes RNA derivatives ob- tained from the sturgeon milts

The list of medicines INN, (Trade name) Medicinal form, dosage Leukopoiesis stimulants Ethyl-carboxyphenyl-thiazolidine-acetate Tabl. 0.002 (Leukogen) Lenograstim Lyoph. pwd. for inj. 33.6 mln U Methyl-oxymethyluracil (Pentoxyl) Tabl. 0.2 Molgramostim (Leukomax) Lyoph. pwd. for inj. 0.000005 Sodium nucleospermate (Polydan) Sol. for inj. 1.5% Leukopoiesis inhibitors Bisulfan (Myelosan) Tabl. 0.002 Mercaptopurine Tabl. 0.05 Glossary Leukopenia is the decreased amount of leukocytes in blood. Leukopoiesis is the process of leukocytes formation and maturation. Lymphogranulomatosis is a malignant tumour of the lymphoid tissue.

XI. MEDICINES AFFECTING THE RESPIRATORY SYSTEM

EXPECTORANTS AND ANTI-TUSSIVE MEDICINES. SURFACTANTS Expectorants are medicines that dilute sputum and relieve its excretion. Expectorants are divided into medicines that stimulate expectoration (secretomotor) and bronchosecretolytic (mucolytics) ones. Anti-tussive medicines are medicines that inhibit cough. Surfactants are medicines, which are surface active substances, they make up the endogenous surfactant deficiency in a disorder of its formation. Classification of medicines Medicines stimulating Mucolytics Anti-tussive medicines expectoration Surfactants Reflex- and resorp- Monocompo- Central- (narcotic and tive*-acting ones nent and com- non-narcotic*), bined* peripheral**-acting ones Althaea* root Ambroxol Codeine phosphate Colphosce- Glycyrrhiza root ryl palmitate Mentoclar Bromhexin hydrochloride Poractant Plantain leaf Althemix Glaucin hydrochloride alpha Inula* root Acetylaminonitropropoxy Bronchophyt benzen**

104 The mechanism of action Medicines stimulating expectoration cause the reflectory (all medicines) and resorptive (Althemix, Inula root, Mentoclar, Althaea root) action on bronchi and bronchial glands. Their expectorant effect is connected with the irritation of receptors of the stomach mucous membrane, where nervous impulses transmit to bronchial glands and muscles and as a result the secretion of bronchial glands, the epithelial fibrillation, peristalsis of bronchioles increases. Sputum is diluted and its secretion is accelerated. Mucolytics activate hydrolyzing enzymes, which decrease the sputum viscosity, and thus, relieve the secretion of sputum from the respiratory tract. Due to its sulphohydryl groups Acetylcysteine breaks disulphidic bonds of acidic glycosaminoglycans of sputum and it leads to the sputum viscosity decrease. Ambroxol, Bromhexin normalize the ratio of serous and mucous components of the bronchial secret; stimulate bronchial glands secretion and the ciliated epithelium activity and promote the removal of the mucous secret. Some mucolytics also stimulate the formation of a surfactant (Ambroxol, Bromhexin). Anti-tussive medicines suppress the cough centre (Codeine phosphate, Dimenoxadol hydrochloride, Glaucin hydrochloride); block afferent receptors of the bronchi, trachea and lung tissue (Acetylaminonitropropoxybenzen) and, thus, inhibit cough. Surfactants make up endogenous surfactant deficiency.

Pharmacodynamics (effects) → Indications Expectorant (all expectorants); Inflammatory diseases of the respiratory mucolytic (mucolytics) tract (acute and chronic tracheitis, bronchitis and pneumonia) Anti-tussive (all anti-tussive medicines) Long-lasting dry non-productive cough Surfactant-like (surfactants) Respiratory distress-syndrome (surfactants, Bromhexin, Ambroxol) Side effects → Contraindications Dyspepsia, hypotension (expectorants, mucolytics, The first trimester of pregnancy anti-tussive medicines) Pulmonary bleedings especially in newborns with Pulmonary bleedings the marked signs of the unripe lungs (surfactants)

The pharmacological “face” of expectorants and mucolytics Medicines Peculiarities Althaea root Coating, AI effects Glycyrrhiza root AI, antiulcer effects Mentoclar AI effect. It contains a complex of volatile oils Plantain leaf AI effect. It is also used in anorexia and hypoacidic states Inula root AI, antiulcer effects Bronchophyt AI, spasmolytic, bactericidal, general tonic, anti-tussive effects. It contains BAS from 12 medicinal plants Bromhexin A weak anti-tussive, surfactant-saving effects. It is a short- acting medicine (It is inactivated quickly)

105 Ambroxol Anti-tussive, surfactant-saving effects. It is also used in the RDS. It is similar to bromhexin by its structure Acetylcysteine It is also used in the RDS. An in poisoning by paracetamol Althemix AI, spasmolytic, antibacterial effects. Syrup: sodium hydrocarbonate, ammonium chloride, sodium benzoate, Anis oil, Althaea root extract Codeine It has all the properties of OA (analgesic effect, etc.) Dimenoxadol It has all the properties of OA (analgesic, cholinolytic effect, etc.) Glaucin Adrenolytic, hypotensive effects. It can be prescribed to children Acetylaminonitropr Disinfectant, local anesthetic effects. In otolaryngology it is opoxybenzen used for preparating to instrumental examination AI – anti-inflammatory; RDS – respiratory distress-syndrome; OA – narcotic analgesics.

The list of medicines INN, (Trade name) Medicinal form, dosage Ambroxol (Ambrobene, Lasolvan) Syrup 0.6%; tabl. 0.03 Althaea root Pwd., infusion, syrup Althemix Syrup 100 ml Acetylaminonitropropoxybenzen (Falimint) Dr. 0.025 Acetylcysteine (ACC) Tabl. 0.1; sol. for inj. 10% Bromhexin Tabl. 0.008 Bronchophyt Pack 100.0 Codeine phosphate Pwd. 0.015 Colphosceryl palmitate (Exosurf) Pwd. 0.108 Dimenoxadol hydrochloride (Estocine) Tabl. 0.005 Glaucin hydrochloride (Glauvent, Tussidil) Tabl. 0.05 Glycyrrhiza root Pack 50.0; 100.0 Inula root Pack 100.0 Mentoclar Sol. 50 ml Plantain leaf Pack 50.0 Poractant alpha (Curosurf) Susp. 8%

Glossary Lung surfactant (the anti-atelectasis factor) spreads as a thin film in the inner surface of lungs, provides stability of the alveolar cells in the breathing process, protects them from negative factors, promotes the regulation of the rheological properties of the bronchopulmonary secret, improves its ―glidence‖ along the epithelium and relieves the secretion of sputum. The respiratory distress-syndrome is the marked respiratory insufficiency (hypoxia), which is connected with the increase of the pulmonary capillaries permeability and with partial outcome into the pulmonary edema.

106 XII. MEDICINES AFFECTING THE METABOLIC PROCESSES

VITAMIN-CONTAINING MEDICINES

Vitamins are organic substances, which one needs to provide the organism’s life activity. They are biologically active even in small quantities. More than 30 vitamins and vitamin-like substances are known. Some of them can be formed in the human body from the vitamin precursors (pro-vitamins) or can be synthesized by the intestinal microflora. Humans receive vitamins mainly with food products. Depending on the extent of the vitamin deficiency in an organism avitaminosis or hypovitaminosis may develop. Hypovitaminoses may be both absolute (the lack of vitamins in food, disorders in vitamin absorption, diseases of the gastrointestinal tract and liver) and relative (a daily need for vitamins increases during pregnancy, lactation, fever) ones. Vitamin medicines are medicines, which are vitamins, their analogues or provitamins according to their chemical structure.

Classification of Vitamins Water-soluble vitamins

Thiamine chloride (B1) Folic acid (Bc) Riboflavin (B2) Ascorbic acid (C) (B5) Nicotinic acid (PP) Pyridoxine hydrochloride (B6) Rutin (P) Cyanocobalamine (B12) Pyridoxalphosphate Pangamic acid (B15) Lipoic acid Fat-soluble vitamins and their water-soluble analogues* (A) Tocoferol acetate (E) Ergocalciferol (D) Menadion (K)* Polyvitamin medicines Vitam MultiTabs Pregnavit Tri-Vi Plus Vitrum Oligovit Revit Undevit Hexavit Pikovit Taxofit Unicap

The mechanism of action The vitamin-containing medicines compensate the vitamin deficiency in the organism and provide the co-enzymes functioning in the enzymatic systems and it stipulates their high activity.

Water-soluble vitamins Pharmacodynamics (effects) → Indications

Thiamine chloride (Vitamin B1) (antineuritic) Cardiotrophic Ischemic heart disease, HF, arrhythmias Neurotropic (regulates the activity Neuralgias, neuroses, beri-beri of mediators and transmission of the nerve impulses) Hypoglycemic Diabetes mellitus

107 Riboflavin (Vitamin B2) Increase of the tissue resistance to Acute hypoxia hypoxia Enhancement of the plasticity Unhealed wounds, burns, hypotrophy, processes and energy formation frostbites Normalization of vision Conjunctivites, ceratites Enhancement of the erythropoietin Anaemias, radiation sickness, leukemia synthesis

Pantothenic acid (Vitamin B5) Improvement of the nerve impulse Neuritis conductivity Participation in the metabolism of Diabetes mellitus, eczema, dermatites, trophic proteins, fats, carbohydrates in ulcers, hepatites, atony of the intestine and oxidation-reduction processes urinary bladder, hypotrophy

Pyridoxine (Vitamin B6) Anabolic Hypotrophy, rickets, tuberculosis Cardiotrophic Myocardiodystrophy, ischemic heart disease Hepatoprotective Hepatites, cholecystitis Detoxication Toxicosis of pregnants, burns, radiation sickness Hemopoietic Anaemias

Cyanocobalamine (Vitamin B12) (anti-anaemic, hemopoietic) Hemopoietic Hyperchromic anaemia, radiation Anti-anaemic sickness, leukemia Activation of the liver function Fatty degeneration of the liver Activation of the nervous system Diseases of the CNS and peripheral function nervous system Regulation of carbohydrate and lipid Dystrophy in children metabolism Pangamic acid (Vitamin B15) Improvement of lipid metabolism Atherosclerosis Increase of the creatine phosphate level Dystrophic damage of the myocardium, in muscles ischemic heart disease Increase of the glycogen content in Hepatitis muscles and liver Antihypoxiс Hypoxia

Folic acid (Vitamin Bc) Stimulation of hemopoiesis Anaemia, radiation sickness, leukemia Improvement of trophism and Tropical sprue regeneration of tissues Nicotinic acid (Vitamin PP) (antipellagric)

108 Antipellagric Pellagra Hypolipidemic Atherosclerosis Reparative Wounds that do not heal for a long time Vasodilating Angiospasms, endarteritis Cardiotrophic Ischemic heart disease Ascorbic acid (Vitamin C) (antiscorbutic) Capillary-protecting, participates in Prophylaxis and treatment of scorbutus, blood coagulation hemorrhagic diathesis, bleedings Antioxidant Atherosclerosis Immune-stimulating Acute and chronic infectious diseases (croupous pneumonia, tuberculosis) Relief of iron absorption from the GIT Hypochromic anaemia; states accompanied by the increased consumption of vitamin C (pregnancy, infectious diseases) Rutin (Vitamin P) Capillary-protecting Hemorrhagic diathesis Antioxidant, antihypoxic Complex therapy of anaemias, IHD Choleretic Cholestasis Lipoic acid Regulation of carbohydrate and lipid Complex therapy of liver diseases metabolism. Lipotropic, detoxication (Botkin's disease, hepatic cirrhosis) Antioxidant IHD, atherosclerosis Side effects → Contraindications Dyspepsia Peptic ulcer, exacerbation of gastritis Hypervitaminosis Hypervitaminosis NB! Pyridoxalphosphate is derivative of pyridoxine with the similar pharmacodynamics and indications.

The list of medicines INN, (Trade name) Medicinal form, dosage Ascorbic acid (Vitamin C) Tabl.0.01; sol. for inj. 5% Calcium pangamate (Vitamin B15) Tabl. 0.05 Calcium pantothenate (Vitamin B5) Tabl.0.01; sol. for inj.10% Cyanocobalamine (Vitamin B12) Tabl. 0.005; sol. for inj. 10% Folic acid (Vitamin Bc) Tabl. 0.015 Lipoic acid Tabl. 0.025; sol. for inj. 0.5% Nicotinic acid (Vitamin PP) Tabl.0.05; sol. for inj. 1% Pyridoxalphosphate Sol. for inj. 0.5% Pyridoxine hydrochloride (Vitamin B6) Tabl. 0.05 Riboflavin (Vitamin B2) Tabl.0.01; sol. for inj. 1% Thiamine chloride (Vitamin B1; Thiamine bromide) Sol. for inj. 6%; dr. 0.05 Vitamin P (Rutin) Tabl. 0.02

109 Glossary Avitaminosis is a significant or total absence of a vitamin in the organism. Beri-beri is a disease caused by vitamin B1 deficiency (polyneuritis). Botkin's disease is infectious hepatitis A. Hemorrhagic diathesis is a group of various diseases characterized by bleedings. Ischemia is decrease of the blood supply of an organ or a tissue. Cardiotonic effect is increase of the myocardial contractility without increase the cardiac rhythm and the oxygen consumption by the myocardium. Cardiotrophic effect is improvement of energy processes, trophism and metabolism in the myocardium that leads to its productivity increase. Keratitis is inflammation of the cornea. Croupous pneumonia is the acute pneumonia with rapid inflammation of the whole lung lobe and the pleura’s adjacent part. Myocardial dystrophy is damage in the structure of the myocardial cells that is connected with disorder of biochemical processes in these cells. Pellagra is a disease connected with deficiency of nicotinic acid, riboflavin and tryptophan and it is characterized by disorders of the skin, GIT and mentality. Tropical sprue is an inflammatory disease of the intestine characterized by the weight loss, anaemia, polyhypovitaminosis. Tuberculosis is an infectious disease caused by mycobacteria. Cholestasis is congestion of bile caused by dysfunction of its outflow. Scorbutus is severe avitaminosis of vitamin C.

Fat-soluble vitamins Pharmacodynamics (effects) → Indications Retinol (Vitamin A) (antixerophthalmic) Regulation of the organism’s growth Complex therapy of rickets, hypotrophies, and development growth disorders in children Normalization of vision Eye diseases (pigmentary retinitis, xerophthalmia) Reparative Skin diseases (burns, wounds, eczema, psoriasis, dermatitis, frostbites, etc.), liver diseases, ulcerous colitis, gastritis, peptic ulcer Increase of the organism’s resistance ARVI, chronic bronchopulmonary diseases and immunity Ergocalciferol (Vitamin D) (antirachitic) Participation in phosphorus and calcium Rickets, osteoporosis, consolidation of metabolism regulation , hypocalcemia, spasmophilia Tocoferol (Vitamin E) (antisterile) Regulation of the reproductive organs Menstrual cycle disorders, sterility, function threatened abortion, dysfunction of sexual glands in men and women Antioxidant, membrane-protective Complex therapy of anaemia, atherosclerosis, IHD, dermatitis, psoriasis Vitamin K (antihemorrhagic) Hemostatic (increase of blood Hemorrhagic diathesis, hemolytic disease coagulation) of newborns, hepatitis, bleedings

110 Side effects → Contraindications Vitamin A Teratogenicity The first trimester of pregnancy Vitamin D Calcification of soft tissues, vascular Heart diseases, hypercalcemia, walls, heart valves pulmonary tuberculosis, hepatic and renal diseases, peptic ulcer Vitamin K Increase of blood coagulation Thromboembolism, the syndrome of hypercoagulation Vitamins A, D, E, K Hypervitaminosis Hypervitaminosis

The list of medicines INN, (Trade name) Medicinal form, dosage Ergocalciferol (Vitamin D) Dr. 500 IU; sol. for inj. 0.5% Menadion (Vitamin K, Vicasol) Tabl. 0.015; sol. for inj. 1% Retinol (Vitamin A, Retinol acetate) Dr. 0.00114 (3300 IU) Tocoferol acetate (Vitamin E) Dr. 0.15; sol. for inj. 5%

Glossary Hemolytic disease of newborns is a congenital disease characterized by intensified lysis of erythrocytes (hemolysis), edemas and anaemia. Dermatitis is inflammation of the skin. Dyspepsia is dysfunction of digestion (nausea, vomiting, diarrhea). Bone consolidation is the process of accreation of the damaged bone. Xerophthalmia is dryness of the conjunctiva. Acute respiratory viral infections (ARVI) are the group of human acute infectious diseases with a primary damage of respiratory organs. Pigmentary retinitis is the inflammation of retina with progressive atrophy and pigmentary infiltration of its internal layers. Psoriasis and eczema are chronic skin diseases. Colitis is the inflammation of the large intestine.

Polyvitamin medicines Abrupt changes of the organism’s physiological state (physical or mental overload, change of climate, pregnancy, aging, etc.) and various pathological processes cause the increased needs in several vitamins. In these cases the states of polyhypovitaminosis can appear. Polyvitamin medicines, as well as complex medicines containing vitamins, are used for stimulation of the organism’s defensive reactions and correction of polyhypovitaminoses.

Pharmacodynamics Polyvitamins assist renewal of the vital tone, increase the immunity, normalize the metabolism, protect the organism from unfavourable environmental affection.

Indications Asthenic states, necessity of the organism’s resistance increase to physical or mental loadings, unfavourable environmental factors. Vitrum, Multi-tabs, Picovit,

111 Taxophyt multivitamins are used in pediatrics; elderly people are given Vitrum, Undevit, Hexavit; pregnant women are taken Pregnavit; Taxophyt, Vitrum, Picovit, Unicap M are used for treatment and prevention of rickets and caries; Tri-Vi-plus is administered for prophylaxis of cancer diseases; Taxophyt, Oligovit, Vitam are used for diseases of the cardiovascular system; Oligovit, Unicap M, Vitam are taken for treatment and prevention of anaemia; Vitrum is used for strengthening of nails and hair.

CORRECTORS OF TISSUE METABOLISM

The metabolism is a complex of biochemical processes that are the base of the vital activities of the organism. Metabolism disorder in tissues is observed in somatic, endocrine, surgical, nervous and other diseases. It can be corrected with the help of many medicines: oxygen, dextrose, aminoacids, microelements, enzymes, anti-enzymes, biostimulants, plasma-substituting solutions, antioxidants, medicines of snake and bee poisons, hormones, vitamins, etc.

Classification of medicines

I. Medicines improving II. Medicines improving III. Biogenic metabolism and energy trophism and the tissue stimulants supply of tissues and regeneration processes and decreasing hypoxia causing cytoprotective* and chondroprotective** effects Oxygen Dextrose Actovegin Solcoseryl Aloe extract Inosine Trimethasidine Cytochrome C* Placenta suspension Adenosine monophosphate Rumalon ** Vitreous body Cocarboxylase Glucosamine ** Kalanchoe juice IV. Medicines containing V. Medicines for parenteral VI. Antioxidants snakes and bees poisons and nutrition and aminoacids products of their vital activity Apilak Methionine Cysteine Erysod Emoxipine Propolis Glutaminic acid Mexidol Apisarthron Cerebrolysine Vitamins C, E, A, P Vipraxine Hydrolysine solution VII. Medicines containing IX. Plasma-substituting micro- and macroelements solutions Calcium chloride Sodium chloride Reopolyglucine Calcium gluconate Neohemodes Potassium iodide Enterodes Sodium chloride Cerebrolecitin

112 Medicines improving metabolism and energy supply of tissues and decreasing hypoxia

Oxygen The mechanism of action is connected with its participation in oxidation- reduction processes providing the tissue breathing.

Pharmacodynamics (effects) → Indications Antihypoxic Hypoxia (but it is not used in the tissue hypoxia) Antihelminthic Ascariasis

Dextrose The mechanism of action It is the energy material that is necessary for biochemical processes, it is easily used by the organism’s cells. It is absorbed and transported in tissues quickly, oxidized there with the energy formation, which is necessary for work of the skeletal muscles, the myocardium, the smooth muscles (especially the intestine) and the brain. Glucose hypertonic solutions increase the blood osmotic pressure that promote the liquid flow from the tissue into blood (the tissue dehydration); the volume of circulating blood increases and its viscosity decreases, that is why glucose decreases edema in tissues and increases the decreased BP. It increases the osmotic pressure because it is not reabsorbable in the renal tubules and that is why it decreases the water reabsorption and increases diuresis.

Pharmacodynamics (effects) → Indications The energy source The medicines dilution, as the blood substitute (Isotonic solution - 5%) Hypertensive It is a component of the antishock liquid. Increase of (Hypertonic solution – the BP in collapse and shock 10-40%) Anti-edemic Life threatening edemas (of lungs and brain) Detoxication Infectious diseases, hepatitis, intoxications Hyperglycemic Hypoglycemia (the insulin overdosage)

Adenosine monophosphate The mechanism of action: it is in the composition of a number of co-enzymes that regulate oxidation-reduction processes. It takes part in the synthesis of nucleic acids and proteins. It decreases the myocardial conductivity.

Pharmacodynamics (effects) → Indications Vasodilating, antihypoxic, anabolic, anti- Obliterating endarteritis, arrhythmic, anti-aggregant thrombophlebitis, venous insufficiency, IHD, tachyarrhythmia

Inosine The mechanism of action: it is a precursor of adenyl and guanyl nucleotides synthesis.

113 Pharmacodynamics (effects) → Indications Antihypoxic, anti-arrhythmic, anabolic IHD, cardiomyopathies, arrhythmias, cachexia, hepatic cirrhosis, radiation- induced leukopenia

Trimethasidine The mechanism of action: it supports the cellular metabolism in ischemia, corrects the ionic transport. Pharmacodynamics (effects) → Indications Antihypoxic, antianginal, cytoprotective IHD, giddiness and hearing disorder of the vascular genesis, Ménière’s disease

Cocarboxylase The mechanism of action: it takes part as a co-enzyme in oxidation-reduction carboxylation and decarboxylation of ketoacids. Pharmacodynamics (effects) → Indications Cardiotrophic effect IHD

Medicines improving trophism and the tissue regeneration processes and causing cytoprotective and chondroprotective effects

Actovegin and solcoseryl The mechanism of action: they improve oxidative phosphorylation, oxygen and glucose utilization, promote the accumulation of macroergic phosphates.

Pharmacodynamics (effects) → Indications Regeneration stimulation and improvement of Dysfunction of the cerebral and the tissue trophism. Solcoseryl has also the peripheral blood circulation, membrane-stabilizing and cytoprotective effect trophic ulcers Actovegin is a deproteinased derivative from the calf blood. Solcoseryl is an extract of the cattle blood.

Cytochrome C The mechanism of action: it is a classic cytoprotector and it stimulates oxidation-reduction reactions. Pharmacodynamics (effects) → Indications Cytoprotective, antihypoxic IHD, hypoxia, dysfunction of the cerebral and peripheral blood circulation, respiratory insufficiency

Rumalon The mechanism of action: it slows down the osteoarthrosis development as it stimulates the synthesis of glycosaminoglycans and of cartilage. Pharmacodynamics (effects) → Indications Chondroprotective Diseases of joints: osteoarthrosis, etc.

114 Glucosamine The mechanism of action: it compensates the deficiency of endogenous glucosamine that is necessary for biosynthesis of proteoglycans and the hyaluronic acid. Pharmacodynamics (effects) → Indications Chondroprotective Osteoarthrosis, osteochondrosis Cardioprotective Prevention of the cardiotoxic effect of medicines Gastroprotective Peptic ulcer

Biogenic stimulants The mechanism of action. For the first time the name of ―biogenic stimulants‖ was proposed by academician V.P. Filatov for substances of animal (placenta suspension, vitreous body) and plant (Aloe ectract, Kalanchoe juice) origin that are able to stimulate metabolic processes and immunity, as well as to accelerate the regeneration processes.

Pharmacodynamics (effects) → Indications Anti-inflammatory, reparative (accelerate Gastro-intestinal, eye diseases, wounds the tissue regeneration)

Medicines containing snakes and bees poisons and products of their vital activity The mechanism of action of bee and snake poisons is not clear enough. It can be explained by the properties of the substances they contain: histamine, hyaluronidase and phospholipase enzymes, choline, tryptophan, microelements, organic acids and others. Bee poison has the reflex action because of the irritation of the skin and subcutaneous tissue receptors.

Pharmacodynamics (effects) → Indications The influence on the vascular Apisarthron (bee poison medicine) is an ointment permeability, microcirculation, that is used in rheumatism, myalgia, sciatica and the BP, the rate of the blood sport traumas. Apilak (a dry substance of the bee flow. Locally irritative (except “milk‖) is used for treatment of hypotrophism and Apilak), anti-inflammatory anorexia in babies and infants. Propolis (a bee effect glue) is used for treatment wounds, burns (ointment), mouth and throat inflammatory diseases (an alcoholic solution). Vipraxine (a water solution of the adder poison) is used locally as analgesic and anti-inflammatory medicine in neuralgia, arthralgia, myalgia, myositis

Nowadays there are a lot of medicines produced on the base of propolis: propolis tincture, ―Propolin‖ tablets, ―Propoceum‖ ointment, ―Proposol‖ aerosol, ―Prostopin‖ suppositories, etc.

115 Medicines for parenteral nutrition and aminoacids

Organic acids that contain aminogroup are found in all cells of the organism both in a free state and in the composition of protein. Aminoacids are an important source of nitrogen in the organism.

Pharmacodynamics (effects) → Indications Methionine is an essential aminoacid that is Lipid dystrophy with the necessary for supporting the body growth and insufficient amount of methionine nitric balance in the organism or toxic damage of the liver Glutaminic acid promotes the ammonium Psychoses, mental deficiency, dehydration encephalitis Cystein is a replaceable acid that is Cataract (because the cysteine synthesized with the help of methionine content is disordered) Cerebrolysine is a complex of neuropeptides Brain traumas, ischemic stroke, from the swine brain. It has the neuroprotector children mental deficiency, senile properties, decreases the neurotoxic effect of dementia the stimulatory aminoacids (glutamate) Hydrolysine solution. It is obtained in the It is a medicine for parenteral acid hydrolysis of the cattle blood proteins nutrition in protein defficiency when adding glucose, it has a detoxication property and it is a source of proteins

Antioxidants

The mechanism of action: antioxidants neutralize toxic free radicals, stimulate endogenous enzymes-antioxidants and thus, inhibit free-radical oxidation (FRO) processes. According to the mechanism of action they are divided into direct-acting antioxidants (direct interaction with free radicals, FRO inhibition) and indirect-acting antioxidants (increasing the activity of the endogenous antioxidant system).

Pharmacodynamics (effects) → Indications Antioxidant is a general pharmacological Therapy of a great number of FRO- effect for all the medicines induced diseases Erysod, Cu-Zn-superoxide dismutase, has It is used in gastroenterology, the anti-inflammatory, anti-ulcer, hepato-, rheumatology, dermatology cardioprotective and other effects Emoxipine, is a derivative of 3- It is used in ophthalmology, oxypyridine, has the antihypoxic, anti- cardiology, neurology aggregant, stress-protective effects, improves microcirculation Mexidol (emoxipine and succinic acid salt) Encephalopathy, acute cerebral blood has the more marked antihypoxic and circulation disorders stress-protective effect, up to the tranquilizing effect, than emoxipine does Vitamins E, C, A, P; selenium, etc. are also widely used as antioxidants in medical practice.

116 Medicines containing micro- and macroelements There are approximately 80 elements of D.I. Mendeleev’s periodic system in human tissues. They are components of enzymes, hormones, vitamins; they are necessary for the synthesis of nucleic acids. Their mechanism of action is stipulated by substitution of their deficiency; pharmacodynamics and indications are related to the physiological role in the organism.

Pharmacodynamics (effects) → Indications Cerebrolecitin is esters of glycerin, Poor bone fracture healing, rickets, phosphoric and fatty acids (it is obtained diseases of the nervous system, anaemia, from the cattle’s brain tissue) glaucoma Medicines containing iodine (iodides) Endemic goiter, hyperthyroidism. are necessary for the normal functioning Operation field preparation in surgery of the organism, the synthesis of and obstetrics, for washing of wounds. thyroxin (the thyroid hormone) that Skin diseases, inflammatory diseases of stimulates metabolism. The molecular the respiratory tract (as expectorants). iodine has the antimicrobial effect; it Syphilis, atherosclerosis. 5% iodine has the ―resolving‖ effect in alcoholic solution, complex iodine atherosclerosis and syphilis; the solution are used. Potassium iodide is an expectorant effect effective mucolytic Medicines containing sodium (the Sodium chloride isotonic solution main intracellular cation) provide the (0.9%) is a blood substituent. constancy of the osmotic pressure, ionic Hypertonic solution is used for balance of the organism’s internal treatment wounds, ulcers, abscesses (it medium, acid-alkaline balance promotes pus removal, causes antimicrobial effect). Sodium hydrocarbonate is an antacid Medicines containing potassium (the Hypokalemia, arrhythmia, overdosage of main intracellular cation) participate in cardiac glycosides, as a diuretic the transmission of the nerve impulses, increase diuresis moderately Medicines containing calcium provide Hypocalcemia, osteoporosis, bone the endurance of the skeleton and teeth, fractures; allergic and inflammatory take part in regulation of the cellular diseases; for increase of blood membrane penetration for sodium and coagulation, the medicines are the potassium (thicken the membranes), components of blood substituents. Of stimulate the heart work (potassium these medicines calcium chloride (it is antagonists), participate in blood introduced intravenously only) and coagulation calcium gluconate are used

Plasma-substituting and detoxication solutions Hydrodynamic disorders in the organism appear when there are intensive bleedings and water-salt balance disorders. For their correction plasma-substituting solutions are used. The intoxication of an organism appears in alcoholism, burns,

117 infectious and tumour diseases, toxicosis in the pregnant women. In these cases detoxication therapy is used.

The mechanism of action By the mechanism of their action these medicines are divided into: a) hemodynamic ones (replenish the blood volume and normalize the blood circulation), b) detoxication ones (bind toxins quickly and eliminate them from the organism), c) regulators of water-salt and acid-alkaline balance.

Pharmacodynamics (effects) → Indications Regeneration of the normal blood Treatment and prevention of shock, acute circulation, decrease of intoxication blood circulation disorders, acute blood loss, states accompanied by intoxication

Reopolyglucine is 10% solution of a low-molecular dextran in the sodium chloride isotonic solution. Neohemodes is 6 % solution of a polyvinylpyrrolidone low-molecular polymer containing also sodium, potassium, calcium, chloride ions. Enterodes is a solution of a polyvinylpyrrolidone low-molecular polymer.

Side effects and contraindications for tissue metabolism correctors Side effects → Contraindications Glutaminic acid - vomiting, diarrhea, Fever, diseases of the liver, kidneys, fissures on lips, excitation. With a GIT, blood-forming organs; the prolonged application the decrease of the increased excitability of the CNS hemoglobin content and leukopenia can be observed Inosine - , redness of the skin, with a Gout prolonged application – exacerbation of gout Adenosine monophosphate - headache, Acute myocardium infarction tachycardia, diuresis increase; in intravenous administration – nausea, redness of the face Liquid Aloe extract injections are painful. Liquid Aloe extract for injections – A feeling of burning can appear while severe diseases of the cardiovascular irrigating the wound with Kalanchoe juice system and kidneys, pregnancy Trimethasidine - nausea, pain in the Trimethasidine – pregnancy, epigastrium, skin itch lactation Solcoseryl in the form of gel can cause Individual intolerance burning of the skin Actovegin - lacrimation (while using eye It is undesirable to use this medicine gel) in the period of lactation Cytochrome C shivering with the increase Individual intolerance of the body temperature (with a rapid introduction)

118 Medicines that contain poisons of bees and Diseases of the kidneys, liver, blood snakes and products of their life activity and pancreas; tumours, severe can cause allergic reactions. Apilak - infectious diseases, brain and disorder of sleep. The feeling of a foreign coronary blood circulation matter in the eye is possible when using eye insufficiency, cardiac malformations, films with apilak sepsis, cachexia, diabetes mellitus, pregnancy. Apilak – Addison’s disease. Propolis – eczema With a rapid i/v administration of Pregnancy and severe renal cerebrolysine the increase of the body dysfunction, the epileptic status temperature is possible Medicines for parenteral nutrition – Neohemodes – bronchial asthma, nausea, vomiting, tachycardia, respiratory acute nephritis, cerebral hemorrhage disorder (with a rapid administration of medicines) When introducing emoxipine into the eye – Pregnancy pain, burning, itching, redness; in systemic administration – drowsiness, hypertension occur Mexidol causes nausea, dry mouth, Marked hepatic and renal drowsiness dysfunctions, allergy to pyridoxin (chemical similarity to pyridoxin) Salt solutions – acidosis, hyperhydration, Salt solutions – thrombocytopenia, increased elimination of potassium from the insufficiency of the blood circulation organism and renal failure. Sodium chloride isotonic solution – hypersodemia, the threat of brain and pulmonary edema; treatment with high doses of . Sodium chloride hypertonic solutions should not be administered subcutaneously and intramuscularly (the tissue necrosis) Medicines containing potassium – nausea, The complete heart block, renal vomiting, diarrhea. With a rapid i/v dysfunction administration of potassium chloride solution the inhibition of the heart functions can appear Medicines containing calcium when Predisposition to thromboses, severe administered intravenously a feeling of atherosclerosis, hypercalcemia, fever appears. With a rapid with cardiac glycosides. administration – bradycardia, ventricular Calcium chloride solution should fibrillation, nausea appear not be administered subcutaneously and intramuscularly (the tissue necrosis)

119 The list of medicines INN, (Trade name) Medicinal form, dosage Actovegin Ointment 5%, sol. for inj. 10% Adenosine monophosphate (Adenocor) Sol. for inj. 3% Aloe (liquid Aloe extract) Syrup; sol. for inj., lin. Apisarthron Ointment Apilak Ointment 3%, tabl. 0.01 Calcium gluconate Tabl. 0.5, sol. for inj. 10 % Calcium chloride Sol. for inj. 5% Cerebrolecitin Tabl. 0.05 Cerebrolysine Sol. for inj. 0.04 g/ml Cocarboxylase (Berolase) Pwd. for inj. 0.05 Cysteine Pwd. 10.0 Dextrose (Glucose, Glucosteril) Sol. for inj. 5%; 40%; tabl. 0.5 Emoxipine Sol. for inj. 1% Enterodes Pwd. per os 5.0, pack Erysod Lyoph. pwd. for inj. 4 mln U Glucosamine (Dona) Pwd. 1.5 Glutaminic acid Tabl. 0.5 Hydrolysine solution Sol. for inj. 450 ml Inosine (Riboxine) Sol. for inj. 0.02 g/ml; tabl. 0.5 Kalanchoe juice Alcoholic sol., vial Mexidol Sol. for inj. 5%, tabl. 0.125 Methionine Tabl. 0.05 Neohemodes Sol. for inj. Oxygen Inhal. sol., balloon Placenta suspension for injections Sol. for inj. Potassium chloride Tabl. 0.5, sol. for inj. 10 % Potassium iodide Tabl. 0.5 Propolis Tinct. 25 ml, vial Reopolyglucine Sol. for infusion Rumalon Sol. for inj. Sodium chloride (Saline solution) Sol. for inj. 0.9% Solcoseryl Ointment 5%, sol. for inj. 10%, tabl. 0.2 Trimethasidine (Preductal) Tabl. 0.02 Vipraxine Sol. for inj. 1 ml Vitreous body Sol. for inj.

Glossary Osteoarthrosis is degeneration of a joint cartilage. Osteochondrosis is a disease that is characterized by a dystrophy in the bone and cartilage tissue. Ventricular fibrillation is the heart arrhythmia with the complete asynchronization of contraction of ventricular myofibrils. Chondroprotective effect is a recovery and protection of the integrity and structure of a joint cartilage.

120 XIII. HORMONAL AND ANTIHORMONAL MEDICINES

Hormonal medicines are medicines that are natural hormones or their synthetic analogues. Antihormonal medicines are medicines that inhibit the production of the certain hormones or have the effects opposite to them.

MEDICINES WITH THE ACTIVITY OF THE HYPOTHALAMUS AND HYPOPHYSIS HORMONES AND THEIR ANTAGONISTS

The hypophysis (pituitary gland) and the hypothalamus form ―neuroendocrine transmission system‖ for the signals that come from the nervous and endocrine system to different organs and tissues. For this purpose the anterior lobe of the hypophysis produces ―tropic‖ hormones: adrenocorticotropic hormone (ACTH), thyrotropic hormone (TTH), somatotropic hormone (STH), follicle-stimulating hormone (FSH), luteinising hormone (LH) and lactotropic hormone (LTH), their synthesis is under control of the hypothalamus releasing factors. The middle lobe of the hypophysis secretes melanocyte-stimulating hormone (MCSH) and the posterior lobe produces oxytocin and vasopressin (antidiuretic hormone - ADH).

Classification of medicines Medicines of the Medicines of the hypophysis hormones Antihormonal hypothalamus Anterior, middle* and posterior** lobe medicines hormones Prothyrelin Corticotropin Somatotropin Gonadorelin Thyrotropin Lactin Bromocryptin Chorionic gonadotropin Menopausal gonadotropin Intermedin* Oxytocin** The mechanism of action Hormonal medicines of the hypothalamus and the hypophysis bind to receptors of target cells, affect the synthesis of RNA and proteins directly (activate the corresponding proteinkinases, etc.). Antihormonal medicines inhibit the secretion of the corresponding hormones of the hypophysis.

Medicines of the hypothalamus hormones Medicines of the hypothalamus hormones have the releasing factors (liberins) activity and stimulate the secretion of tropic hormones of the anterior lobe. Pharmacodynamics (effects) → Indications Prothyrelin stimulates the secretion of Diagnosis of the thyroid gland TTH, LTH insufficiency in patients with hypothyroidism, hypogalactia Gonadorelin stimulates the secretion of Substitution therapy in deficiency of LH, FSH (promotes the maturing of endogenic LH, in retardation of male follicles and , increases and female puberty, ovarian spermatogenesis) dysfunction

121 Side effects → Contraindications Prothyrelin increases the muscular tone Diseases of the CNS, epilepsy, and blood pressuse, decreases vision ischemic heart disease, hypertension, pregnancy Gonadorelin causes dyspepsia, painful Diseases of the GIT, uterine bleedings menstruations

Medicines of the hypophysis anterior lobe Pharmacodynamics (effects) → Indications Corticotropin (ACTH) stimulates the The secondary hypofunction of the synthesis of and partially adrenal cortex, prevention of the ; has the anti-inflammatory, adrenal glands deficiency after anti-allergic, immunosuppressive effects glucocorticoids usage Somatotropin (STH) increases the Hypophysal nanism skeleton growth, the body weight, has the anabolic effect Menopausal gonadotropin (FSH+LH) Male and female sterility promotes the development of ovaries and maturing follicles there, increases spermatogenesis Chorionic gonadotropin (LH) causes the Sexual infantilism, follicle’s coming to the yellow body; caused by hypothalamus and stimulates the production in hypophysis dysfunction, women, activates the function of testes cryptorchidism, the menstruation cycle and the synthesis in men dysfunction, spontaneous abortion Lactin increases the lactation in the Hypogalactia postnatal period; promotes deposition of fat in the body Side effects → Contraindications Somatotropin, chorionic gonadotropin, Oncologic diseases corticotropin stimulate the development of metostases Corticotropin causes hyperglycemia, Diabetes mellitus, severe hypertension, edemas, blood pressure increase, peptic and duodenal ulcer, ulceration of the GIT osteoporosis, pregnancy Somatotropin causes hyperglycemia Diabetes mellitus NB! Gonadotropins are used under the strict medical control because of the possible acute increase of the ovaries size and the increased secretion of estrogens.

Medicine of the hypophysis middle lobe Intermedin is a medicine with the activity of the melanocyte-stimulating hormone. Pharmacodynamics (effects) → Indications Stimulation of the eye’s cones and rods, increase of Degenerative changes the acuity of vision, improvement of the eye’s adaptation of the eye’s retina, to darkness pigmentary retinitis

122 Medicine of the hypophysis posterior lobe (oxytocin)

Pharmacodynamics (effects) → Indications Stimulation of uterine contractions and Labour induction, hypotonic uterine development of mammary glands; in bleedings after labour high doses – spastic uterine contractions Side effects → Contraindications Hypertone of the uterus, preterm Increase of the uterine tone, anatomically placental detachment narrow pelvis, anomalous position of the fetus, uterine scar

Hypophysal hormones secretion inhibitors

Pharmacodynamics (effects) → Indications Danazol inhibits secretion of the Endometriosis, benign mammary gland hypophysal gonadotropins (FSH and tumours, gynecomastia LH), causes atrophy of the endometrium Bromocryptin inhibits the secretion of Menstrual cycle disorders accompanied the hypophysal STH and LTH by hyperprolactinemia and acromegalia Side effects → Contraindications Danazol – alopecia, dysmenorrhea, Tumours of the reproductive system, edema, increase of the ICP epilepsy Bromocryptin – orthostatic Hypotension hypotension The list of medicines INN, (Trade name) Medicinal form, dosage Bromocryptin Tabl. 0.025 Chorionic gonadotropin (Pregnyl) Pwd. for inj.1000 IU Corticotropin Pwd. for inj. 40 IU Danazol (Danol) Caps. 0.1 Gonadorelin Pwd. for inj. 0.00073 Intermedin Pwd. for inj. 0.05 Lactin Pwd. for inj. 100 U Menopausal gonadotropin Pwd. for inj.75 U Oxytocin Sol. for inj. 5 U/ml Prothyrelin Pwd. for inj. 0.005 Somatotropin Pwd. for inj. 4 IU Thyrotropin Pwd. for inj.

Glossary Acromegalia is increase of extremities and features of the face connected with hypersecretion of STH after a human stops growing. Alopecia is a constant or temporary loss of hair. Gynecomastia is increase of mammary glands in males. Hypogalactia is a decreased secretion of mammary glands during the period of lactation. Hypogonadism is a decreased secretion of gonads with a weak development of genitals and secondary sexual features. Hypothyroidism is

123 insufficient production of . Hypophysal nanism (dwarfism) is a syndrome characterized by small stature in comparison to the sexual and age norm. Hirsutism is an excessive pilosis of female by male type. Gonadotropins are protein and peptide hormones (FSH, LH) that affect the function of female and male gonads. Infantilism is either mental and/or physical retardation. Cryptorchidism is the lack of either one or both of testicles in the scrotum, because they do not descent from the abdominal cavity. Ovulation is ovum’s leaving from a follicle.

INSULIN-CONTAINING MEDICINES AND SYNTHETIC HYPOGLYCEMIC MEDICINES

Insulins The endocrine part of the pancreas contains about 2 million of Langerhans islets consisting of alpha- and beta-cells that secrete glucagon and insulin, respectively. Insulin and glucagon influence on the metabolism of carbohydrates: insulin has the hypoglycemic activity; glucagon (insulin antagonist) has the hyperglycemic activity. The physiological activity of these two hormones is directed to more complete utilization of glucose by tissues. Glucose is the most powerful and specific stimulant of the synthesis and secretion of insulin. Absolute or relative insulin deficiency, as a result of the hypofunction of beta- cells of Langerhans islets, causes diabetes mellitus – an endocrine and metabolic disease characterized by disorders of all kinds of metabolism processes, especially it refers to disorders of the carbohydrate metabolic that leads to progressive increase of the glucose level in blood (hyperglycemia) and its excretion by the urine (glucosuria). Diabetes mellitus also develops when insulin is produced in sufficient amount but it is rapidly inactivated by insulinase. There are two types of diabetes mellitus: type I (insulin-dependent) and type II (insulin-independent). Comatose states such as hyperketonemic coma (diabetic or hyperglycemic) and hypoglycemic coma belong to acute complications of diabetes mellitus.

Classification of medicines Human insulins and their analogues* Short-acting Medium-acting Long-acting Insulin lispro* Human insulin Human insulin Human insulin Insulin glargin Insulin aspart* Insulins of animal origin Short-, medium- and long-acting ones Porcine insulin Combination of short- and medium-acting insulins Human ones Animal ones Human insulin Porcine insulin

The mechanism of action Insulin interacts with insulin receptors of cell membrane (liver, muscles, adipose tissue) forming the ―insulin + receptor‖ complex that penetrates inside the

124 cell, where release of insulin takes place. Insulin regulates the protein and carbohydrate metabolism, lipid metabolism (increase of lipogenesis, decrease of lipolysis), affects the water-electrolyte exchange (reduces the loss of liquid by the organism).

Pharmacodynamics (effects) → Indications Hypoglycemic effect (decrease of Diabetes mellitus type I, hyperglycemic glycolysis, gluconeogenesis, increase of coma glycogenesis from glucose in the liver, muscles) Anabolic effect (increase of protein Cachexia synthesis) Side effects → Contraindications Hypoglycemic state (feeling of hunger, Hypoglycemia, acute hepatitis, hepatic sweating, weakness, dizziness, cirrhosis, hemolytic jundance, tachycardia) pancreatitis, cardiac malformations

The pharmacological “face” of insulins Medicines Origin Action start duration, h Ultra-short-acting Insulin lispro Analogue of 5-15 min 3-4 human insulin Insulin aspart Analogue of 10-30 min 3-5 human insulin Short-acting Human insulin Human 30 min 9 Medium- acting Porcine insulin Animal 30-60 min 8-20 Long-acting Insulin glargin Analogue of 3-4 h 24-28 human insulin

The list of medicines INN, (Trade name) Medicinal form, dosage Human insulin (Humulin) Susp. for inj. 100 U/ml Insulin lispro (Humalog) Sol. for inj. 100 U/ml Insulin aspart (Novorapid) Sol. for inj. 100 U/ml Insulin glargin (Lantus) Sol. for inj. 100 U/ml Porcine insulin (Pharmasulin, Monodar) Susp. for inj. 100 U/ml

Glossary Glycolysis is decomposition of glycogen in the liver to glucose-6-phosphate and glucose. Gluconeogenesis is the glucose synthesis from non-carbohydrate substances (aminoacids). Cachexia is the extreme degree of the organism’s exhaustion and emaciation accompanied by the acute asthenia and apathy.

125 Peroral hypoglycemic medicines

Classification of medicines Derivatives of sulphonylurea biguanides thiazolidinones 1st generation 2nd generation 3rd generation Metformine Rosiglytazone Glybenclamide Glymepiride Buformine Pyoglytazone Glyquidone Glypiside Medicines of different groups (meglytinides, α- glycosidase inhibitors*) Acarbose* Repaglynide

The mechanism of action Sulphonylurea derivatives and meglytinides stimulate secretion of endogenous insulin by β-cells of the pancreas. Biguanide derivatives increase binding of insulin to the insulin receptors, inhibit intestinal absorption of glucose and gluconeogenesis in the liver, decrease the level of glucagon in blood. Thiazolidinones eliminate peripheral insulin resistance. α-Glycosidase inhibitors block α-glycosidase of the GIT, disturb polysaccharides breakdown to monosaccharides and their absorption.

Pharmacodynamics (effects) → Indications Hypoglycemic Diabetes mellitus type II. Diabetes Hypocholesterolemic mellitus type I in patients taking insulin Anorectic and suffering from obesity Side effects → Contraindications Hypoglycemia, meteorism, diarrhea, Hypoglycemic coma, precomatose states, increase of body weight, lactacidosis diabetes mellitus type I in children, marked hepatic and renal dysfunctions, pregnancy, lactation

The pharmacological “face” of peroral hypoglycemic agents Medicines Generation Hypoglycemic T1/2, h Action, h effect start duration Tolbutamide I 1 5-6 1 10-12 Carbutamide – «- ++ 36 5 12 Buformine – «- 3-7 2-3 8 Metformine – «- ++ 6-17 2 16 Glybenclamide II 150-200 4-11 1,5-2 18 Glyquidone – «- +++ 1,5 1-2 8-12 Glymepiride – «- 200-250 5-8 2-3 24 Glypiside – «- 2-5 30 min >24 Pyoglytazone III 3-7 2-3 24 Repaglynide – «- 1 1,5-2 12 Rosiglytazone – «- 3-4 30-40 min 10-12

126 The list of medicines INN, (Trade name) Medicinal form, dosage Acarbose (Glucobay) Tabl. 0.05 Buformine (Glybutide) Tabl. 0.05 Carbutamide (Bucarban) Tabl. 0.5 Glybenclamide (Maninyl) Tabl. 0.005 Glyquidone (Glurenorm) Tabl. 0.03 Glymepiride (Amaril) Tabl. 0.003 Glypiside (Minidiab) Tabl. 0.005 Metformine (Glucophag) Tabl. 0.5 Pyoglytazone (Pyonorm) Tabl. 0.03 Repaglynide (NovoNorm) Tabl. 0.0005 Rosiglytazone (Avandia) Tabl. 0.008 Tolbutamide (Butamide) Tabl. 0.05

Glossary Hypoglycemic coma is a coma caused by abrupt decrease of glucose level in blood (for example, after insulin overdosage). Diabetic (hyperglycemic) coma is a coma caused by an acute deficiency of insulin in diabetes mellitus.

THYROID HORMONES MEDICINES AND ANTITHYROID AGENTS

Thyroid hormones (thyroxine, tri-iodthyronine) stimulate the growth processes, intensify the activity of the sympathetic nervous system. Thyrocalcitonin and parathyroid hormone regulate the calcium metabolism. Dysfunction of the thyroid gland can occur by either hypothyroidism or hyperthyroidism. Hypothyroidism (mixedema, cretinism, endemic goiter) can be caused by dysfunction of hypothalamic and hypophysal system or by direct dysfunctions of the thyroid gland. Hyperthyroidism occurs when the increased secretion of thyroid hormones takes place.

Classification of medicines Thyroid ones Antithyroid ones (thyroid hormones medicines) (thyreostatics) Mono-component Combined Thyroidine Thyrocomb Thiamazole Levothyroxine sodium Thyrotom Propylthiouracil Lyothyronine Novothyral

Thyroid medicines The intake of thyroid medicines is one of the basic methods of hypothyroidism treatment.

The mechanism of action The substitutive effect of thyroid medicines is stipulated by the presence of thyroxine and tri-iodthyronine in their composition. These hormones bind to receptors

127 of target cells and, as a result, they increase the synthesis of RNA and proteins changing the function of cells, tissues, organs and systems.

Pharmacodynamics (effects) → Indications Increase of the basal metabolism, Primary hypothyroidism, mixedema, growth and tissue differentiation, energy cretinism, endemic goiter. Cancer of the processes, tissue need in oxygen. thyroid gland, hypothyroid obesity. Anabolic, catabolic (in high doses) Prophylaxis of goiter’s recurrence after effects the thyroid resection Side effects → Contraindications Stimulation of the CNS, perspiration, Thyrotoxicosis, cachexia, tachycardia, tremor, the loss of weight, heartaches, ischemic heart disease tachycardia

The pharmacological “face” of thyroid medicines Medicines Efficiency Composition/peculiarities Thyroidine + Thyroxine + tri-iodthyronine Levothyroxine sodium + Synthetic left-rotating isomer of thyroxine, has an effect in 7-12 days Lyothyronine ++ Effect develops in 6-8 h Thyrocomb +++ Lyothyronine + levothyroxine + iodine Thyrotom +++ Lyothyronine + levothyroxine

Antithyroid medicines Antithyroid medicines inhibit the formation and release of the thyroid gland hormones.

The mechanism of action They inhibit the synthesis of the thyroid gland hormones suppressing the enzymatic systems activity (peroxidases) that take part in this process.

Pharmacodynamics (effects) → Indications Thyreostatic (decrease of the thyroid Hyperthyroidism, thyreotoxicosis, diffusion gland hormones synthesis), decrease of toxic goiter the basal metabolism Side effects → Contraindications Spreading and increasing of Hypothyroidism, nodular goiter, inhibition vascularisation of the thyroid gland (a of blood cells formation (leukopenia, strumogenic effect). Leukopenia, agranulocytosis) agranulocytosis

The list of medicines INN, (Trade name) Medicinal form, dosage Levothyroxine sodium (L-Thyroxine) Tabl. 0.005 Lyothyronine (Tri-iodthyronine) Tabl. 0.0005

128 Novothyral Tabl. Propylthiouracil (Propycil) Tabl. 0.05 Thiamazole (Mercazolyl) Tabl. 0.005 Thyroidine Tabl. 0.05 Thyrocomb Tabl. Thyrotom Tabl.

Glossary Toxic goiter (thyreotoxicosis, hyperthyroidism, Graves’ disease, Basedow’s disease) is a disease that is characterized by diffusion overgrowth of the thyroid gland and the increased secretion of thyroid hormones, which cause dysfunction of all kinds of metabolism, energy and functions of different organs. Cretinism is a syndrome of the inborn insufficiency of the thyroid gland function with the acute retardation of physical and psychic development. Mixedema is an edema (all over the body) of the subcutaneous tissue in hypothyroidism. The basal metabolism is the marker of the energy exchange intensity (kcal/24 hours or kcal/hour). Peroxidases are enzymes that catalyze the oxidation-reduction reactions. Endemic goiter is the increase of the thyroid gland due to the decreased content of iodine in water and food.

MEDICINES OF THE PARATHYROID GLANDS HORMONES AND MEDICINES REGULATING CALCIUM LEVEL IN THE BODY Normal calcium concentration in the body is controlled by parathormone (that stabilizes the calcium ions concentration in blood if it is decreased); by calcitonin (that normalizes the calcium level in blood if it is increased); by the active form of vitamin D – D3 (that restores the calcium absorption in the intestine if its concentration decreases in the blood plasma). Parathyroid glands take part in the exchange of calcium and phosphorus producing parathormone. When decreasing the calcium concentration in blood the parathormone secretion intensifies. The excess of calcium in blood leads to inhibition of the parathormone release.

The list of medicines Parathyroidine Calcitonin

The mechanism of action They interact with target-organs (bone tissue, intestine, kidneys) and stabilize the calcium level in blood and bones: calcitonin inhibits bone resorption; parathyroidine (parathormone) increases bone resorption.

Pharmacodynamics (effects) → Indications Parathyroidine It promotes calcium release from bones and Prophylaxis of tetany in hypo- increase of its amount in blood, intensifies parathyroidism, diseases caused by the calcium absorption by the intestinal disorder of the phosphorus-calcium mucous membrane, its reabsorption in renal exchange (spasmophilia, hypo- tubules; retains reabsorption of phosphates calcemic convulsions, etc.)

129 Calcitonin It regulates calcium and phosphates Osteoporosis, hypercalcemia, pain in exchange in the body, promotes the bones, Paget’s disease, osteomyelitis, transition of phosphates and calcium from paradontosis, hypervitaminosis D, blood to the bone tissue slow inosculating of fractures Side effects → Contraindications Parathyroidine Hypercalcemia Increased amount of calcium ions in blood Calcitonin Hypocalcemia Decreased amount of calcium ions in blood

The list of medicines INN, (Trade name) Medicinal form, dosage Calcitonin (Calcitrin) Sol. for inj. 50 U Parathyroidine (Parathormone) Sol. for inj. 20 U/ml

Glossary Paget’s disease is deforming osteitis. Hypoparathyroidism is hypocalcemia when parathormone is insufficient. Osteoporosis is dystrophy of the bone tissue with the complete resolution of some bone cross-pieces. Spasmophilia is the combination of the increased neuro-muscular excitability with the laryngospasm. Tetany is attack of tonic convulsions.

MEDICINES OF ADRENAL GLANDS CORTEX HORMONES

Mineral corticoids (MC) Desoxycorticosterone acetate Glucocorticoids (GC) Systemically- Local-acting ones acting ones for inhalation for external and combined intranasal use medicines Budesonide Hydrocortisone Aurobin Dexamethasone Budesonide Trimistine Mazipredone Triamcinolone Dexamethasone Triamcinolone Flunisolide Triamcinolone Fluocinolone acetonide

Mineral corticoids

The mechanism of action Penetrating into the cellular cytoplasm of the renal distal tubules MC bind to the cytoplasm receptors forming the hormone-receptor complex. This complex penetrates into the nucleus and stimulates the synthesis of permease protein that promotes the reabsorption of Na+ from urine.

130 Pharmacodynamics (effects) → Indications Regulation of water-salt Primary and secondary insufficiency of metabolism: increase of the blood adrenal cortex (hypocorticism, Addison’s + pressure, retention of Na , H2O and disease) elimination of K+ Normalization of the tone and Myasthenia improvement of the skeletal muscles activity Side effects → Contraindications Edema, increase of BP, Hypertension, heart failure, treatment with hypokalemia, increase of loop and thiazide diuretics, glaucoma intraocular and

Glucocorticoids

The mechanism of action The mechanism of action of glucocorticoids (GC) is similar to the mechanism of action of other steroid hormones. The hormone-receptor complex penetrates into the nucleus where influencing on the genetic apparatus it affects the protein synthesis processes. The metabolic effects of GC such as the influence upon all kinds of metabolism in the body (protein, carbohydrate, lipid, water-salt ones) are determined by the activation of the synthesis of some proteins and the inhibition of the synthesis of others.

Pharmacodynamics (effects) → Indications Protein metabolism: increase of the Substitution therapy of chronic and protein disintegration, inhibition of their acute adrenal insufficiency synthesis (hypocorticism, Addison’s disease) Carbohydrate metabolism: decrease of glucose coming to cells, hyperglycemia Lipid metabolism: stimulation of the lipid synthesis from glucose and the fat deposition in the region of face, the upper part of the trunk and in the lower extremities, increase of appetite. Collagenoses, glomerulonephritis, acute Anti-inflammatory, immunosuppressive, pancreatitis, organ transplantation, severe anti-allergic, antishock, antitoxic effects allergic reactions, shock Side effects → Contraindications Water retention, ↑BP, ―steroid‖ diabetes, Severe hypertension, diabetes mellitus, ulcer, psychosis; muscle weakness, peptic ulcer, osteoporosis, psychic gastric bleedings, osteoporosis, increased dysfunctions, predisposition to thrombo- blood coagulability, body weight increase ses, Itsenko-Cushing disease, pregnancy

NB! GC taking as anti-inflammatory medicines are administered only in the case when all other possible therapies do not give result. Fluorine-containing medicines are the most effective GC for local application. A sudden stoppage of usage of GC provokes the syndrome of ―rapid discontinuation‖ and that is why it is

131 necessary to decrease their dose gradually under doctor`s supervision. The term of a gradual withdrawal can last for some months. Corticotropin is administered 3 days before the stoppage of medicines usage.

The pharmacological “face” of glucocorticoids The Anti- Na+ Medicines duration inflammatory Other peculiarities retention of action effect Hydro- Short 1 1 It is used both cortisone (5-12 h) systemically and locally Flunisolide Short -//- 200-300 0 Aerosol Fluocinolone Short -//- 25-30 0 Ointment (is used on the acetonide limited sites of the skin) Aurobin Short -//- 4 0 Ointment (mazipredone, lidocaine, triclosan) for hemorrhoid treatment Mazipredone Middle 4-5 0.8 Water soluble synthetic (12-30 h) prednisolone derivative Budesonide Middle 4 0 It is similar to -//- triamcinolone Triamcino- Long 5 0 It is used systemically lone (36-72 h) and locally Dexametha- -//- 25-30 0 A strong anti-allergic sone effect

The list of medicines INN, (Trade name) Medicinal form, dosage Aurobin Ointment, tube 20.0 Budesonide (Apulein, Pulmicort) Tabl. 0.0005; sol. 0.025%; oint. 0.025% Desoxycorticosterone acetate (DOCSA) Tabl. 0.005; sol. for inj. 2.5% Dexamethasone (Dexalone) Tabl. 0.004; sol. 0.4% Flunisolide (Ingacort) Aerosol 0.25 mg/day; gel 0.25 mg/g Fluocinolone acetonide (Sinalar, Gel 0.025% Synaflan, Flucinar) Hydrocortisone (Hydrocort, Locoid) Cream 2.5%; sol. for inj. 2.5% Mazipredone (Depersolone) Sol. for inj. 3%; ointment 0.25% Triamcinolone (Kenalog) Tabl. 0.008; sol. for inj. 4%; cream 0.1% Trimistine Ointment, tube 10.0

Glossary Itsenko-Cushing disease is a hyperproduction of endogenous cortisol in adrenal hyperplasia (obesity, diabetes, hypertension, in women, osteoporosis, etc.). Collagenoses are autoimmune diseases with diffusive damage of the connective tissue and vessels. Myasthenia is the muscular weakness. “Steroid” diabetes, ulcer, psychosis are development of hyperglycemia, ulcerations of the GIT, disorders of the CNS caused by GC administration.

132 MEDICINES OF THE SEXUAL HORMONES. ANABOLIC . ANTAGONISTS OF THE SEXUAL HORMONES

Classification of medicines Female Male Anabolic Estrogens Gestagens (androgens) steroids Estron Allylestrenol Testosterone decanoate Progesterone Methyltestosterone Methylandrostendiol Hexestrol

MEDICINES OF THE FEMALE SEXUAL HORMONES

Medicines of estrogens

Estrogens are medicines containing the female sexual hormones produced by follicles and their synthetic analogues.

The mechanism of action Estrogenic medicines accumulate selectively in target organs: uterus, vagina, mammary glands, anterior lobe of the hypophysis, liver where they bind to specific extranuclear protein – estrophyllin, receptors of plasmatic membranes of target cells forming hormone-receptor complexes, which penetrate into the nucleus, influence on the protein synthesis (activating the DNA and RNA synthesis).

Pharmacodynamics (effects) → Indications Estrogenic effect: The insufficient function of - stimulation of development of the sexual ovaries (amenorrhea, dysmenor- organs and the secondary female sexual rhea, climacterium, sterility), characters; hypoplasia of the genitals and - proliferation of the endometrium during the underdevelopment of the first part of the menstrual cycle; secondary sexual characters - increase of the uterine contractility and tone Labour induction Side effects → Contraindications Cystic degeneration of ovaries, Tumours of uterus and ovaries, cystic carcinoma of the uterus and the mastopathies, uterine bleedings, severe mammary gland, uterine bleedings, forms of hypertension, pregnancy, edema, hypertension lactation

The pharmacological “face” of estrogenic medicines Medicines Activity Duration Other peculiarities of action Estron + + It is obtained from female and animal urine Estradiol ++ +++ It is used once per 2 days Hexestrol + It has the non-steroid structure

Medicines of gestagens Gestagens are medicines containing the female sexual hormones produced by the yellow body, placenta, as well as their synthetic analogues.

133 The mechanism of action Gestagens interact with progestine receptors located in target organs (the reproductive organs) and in the brain. It leads to changes in the synthesis of DNA, RNA, proteins and appearance of the gestagenic effect.

Pharmacodynamics (effects) → Indications Gestagenic effect: Endocrine forms of infertility, dysfunction - stimulation of the endometrium’s of the menstrual cycle, habitual abortions, secretory phase in the second part of threatened preterm labour, peroral the menstrual cycle; contraception - preparation of the endometrium to implantation of the impregnated ovum; - inhibition of the hypophysis gonadotropic function (in high doses); - decrease of the uterine contractility Side effects → Contraindications Increase of BP, acne, hirsutism, libido Hypertension, uterine bleedings, hormone- changes, body weight increase dependent cancer of the mammary gland and the genitals

The pharmacological “face” of gestagenic medicines Medicines Activity Peculiarities Allylestrenol ++ It is a medicine for peroral use Progesterone + A short-acting, as it is quickly destroyed

MEDICINES OF THE MALE SEXUAL HORMONES

Androgens Androgens are medicines containing hormones produced by the male sexual glands, adrenal cortex, and their synthetic analogues.

The mechanism of action The mechanism of action of androgens is based on their interaction with cytosol testoid receptors located in target organs (the prostate, testis and their epoophorons, skeletal muscles, etc.). After binding to androgens the receptor conformation changes and the changes in DNA and RNA functions take place leading to the synthesis of different functional proteins (enzymes, etc.).

Pharmacodynamics (effects) → Indications Androgenic effect: Infertility, infantilism, impotency, - stimulation of development of the genitals pathological male climacterium, and the secondary male sexual characters; malignant tumours of the mammary - providing the reproductive function; gland and ovaries in women (up to - regulation of spermatogenesis, potency, 60 years old) libido after puberty of the organism Moderate anabolic effect

134 Side effects → Contraindications Edema, BP increase, prostate hyperplasia, Hypertension, , hypercalcemia, spermatogenesis dysfunc- hypercalcemia, renal and hepatic tion, musculinisation (in women), insufficiency, pregnancy, for men over hepatotoxicity 65 years old

The pharmacological “face” of androgens

Medicines Activity Origin Peculiarities Testosterone +++ natural It is introduced parenterally Methyltestosterone + synthetic It is stable in the GIT

Anabolic steroids Anabolic steroids (AS) are synthetic derivatives of the male sexual hormones that unlike the natural androgens have a significantly decreased androgenic and a high anabolic effect.

The mechanism of action AS penetrate into the cytoplasm of target organs cells (skeletal muscles, myocardium, kidneys, liver, lungs, etc.), are transported into the nucleus interacting with DNA and RNA, regulate the protein synthesis, as well as hormones with the polypeptide structure. Under the influence of anabolic steroids the increase of the cell breathing intensity and oxidative phosphorylation, accumulation of macroergic phosphates, secretion of the STH are observed.

Pharmacodynamics (effects) → Indications Anabolic effect (stimulation of the Cachexia, hypotrophy; radiation and protein synthesis, retention of nitrogen, therapy, burns, myocardial calcium, phosphorus in the body) infarction, osteoporosis, traumas Moderate androgenic effect Side effects → Contraindications Hepatotoxicity, cancerogenic effect, Liver and kidney diseases, prostate edema, BP increase, hypercalcemia, cancer, hypertension, hypercalcemia, hyperglycemia, hyperlipidemia epilepsy, pregnancy, lactation, for children

The pharmacological “face” of anabolic steroids Medicines Activity The duration of action ++ +++ Methylandrostendiol + +

The list of medicines INN, (Trade name) Medicinal form, dosage Allylestrenol (Turinal) Tabl. 0.005 Estradiol (Proginova) Tabl. 0.001; TTS 25 mcg Estron (Folliculin) Sol. for inj. 0.1% Hexestrol (Synestrol) Tabl. 0.001 Methylandrostendiol (Methandriol) Tabl. 0.01 Methyltestosterone Tabl. 0.01

135 Nandrolone decanoate (Retabolil) Sol. for inj. 5% Progesterone Caps. 0.1 Testosterone propionate Caps. 0.04; sol. for inj. 1%

Glossary Amenorrhea is the absence of menstruations. Hirsutism is an excessive hairiness in women by the male type. Musculinisation (syn. virilization) is the appearance of the male features in women while using androgens (gruff voice, increased hairiness, etc.).

Antagonists of the sexual hormones

Classification of medicines Anti-estrogenic Antigestagenic Anti-androgenic Clomiphencitrate Miphepristone Cyproterone

The mechanism of action Anti-estrogens bind to receptors competitively in the hypothalamus and ovaries and it leads to the more intensive release of gonadotropins (according to the negative feedback principle) causing maturation of follicles. In addition, by binding to estrogenic receptors in a tumour cell they block the activity of estrogens. Antigestagens block progestin receptors in the uterus and prevent progesterone’s influence on them. Anti-androgens (in particular, Cyproterone) inhibit competitively cytoplasmic androgenic receptors in target cells, decrease the action of the male sex hormones.

Pharmacodynamics (effects) → Indications Anti-estrogens Ovulation stimulation, inhibition Anovulatory sterility, breast cancer, of estrogen-dependent tumours endometriosis, dysfunctional uterine bleedings Antigestagens Antigestagenic (in particular, Interruption of pregnancy at early stages uterotonic) effect (medical abortion) Anti-androgens Anti-androgenic (decrease of potency, decrease Androgenization in women, of spermatogenesis, inhibition of - preterm puberty in boys, non- dependent tumours growth) effect operative prostate carcinoma Side effects → Contraindications Anti-estrogens Thromboses, hypercalcemia, edema, ovarian Thromboembolic states, hypercalce- hyperstimulation syndrome, metrorrhagia mia, uterine bleedings, pregnancy Antigestagens Dizziness, weakness, fever, dyspepsia, metrorrhagia Bleeding, pregnancy Anti-androgens Changes in body weight and libido, Spermatogenesis disorder, pregnancy, depression, gynecomastia, spermatogenesis edema, thromboses, liver function disorder, edema, thromboses, hepatotoxicity disorders, age under 18

136 NB! With a low level of endogenous estrogens in the organism anti-estrogenic medicines have a moderate estrogenic effect, while with a high level they have the anti-estrogenic effect.

The list of medicines INN, (Trade name) Medicinal form, dosage Clomiphencitrate (Clomiphene) Tabl. 0.05 Cyproterone (Androcur) Tabl. 0.01 Miphepristone (Penkrofton) Tabl. 0.2

Glossary Metrorrhagia is the uterine bleeding. Endometriosis is a benign prolifiration of the endometrium tissue outside the uterus. Ovulation is the process when a mature ovum comes from the follicle.

CONTRACEPTIVES

Contraceptives are medicines used to prevent undesirable pregnancy.

Classification of medicines Combined (estrogen-gestagen) Microdoses of gestagens monophasic biphasic tri-phasic (mini-pills) Ovidon Antiovin Tri-regol Linestrenol Logest Triquilar Postcoital Vaginal contraceptives (spermicides) Benzalkonium chloride

The mechanism of action By the negative feedback principle combined estrogen-gestragen contraceptives block the release of hypothalamus hormones and the gonadotropic hormones of the hypophysis anterior lobe (FSH and LH), and, therefore, they inhibit the central regulation mechanism of the ovule maturation. Gestagens suppress development of follicles in the ovary, cause the thickening of the cervical mucus that prevents spermatozoons penetrating into the uterine cavity; besides, they cause changes in the endometrium preventing the implantation of the fertilized ovum. The contraceptive effect of mini-pills is based on the following factors:  the ―cervical‖ factor is decrease of the amount of the cervical mucus and change of its physical and chemical properties (increase of viscosity), as a result the spermatozoons penetrating ability decreases;  the ―uterine‖ factor is inhibition of the endometrium proliferation, ovum implantation altering;  the ―tubal‖ factor is inhibition of the peristaltic contractions of the Fallopian tubes that hamper the ovum’s transport. The inhibiting influence of gestagens microdoses on the hypothalamus and hypophysis system is less compared to that of the combined peroral contraceptives. Postcoital contraceptives inhibit ovulation, change the normal course of the secretory phase of the menstrual cycle, cause temporary atrophic changes in the ovaries.

137 Spermicides disturbing the cell membrane cause fragmentation and destruction of spermatozoons.

Pharmacodynamics (effects) → Indications Contraceptive (for all medicines), anti-ovulatory (for Contraception hormonal medicines); spermicidal (for spermicides) effect Side effects → Contraindications Estrogen-dependent complications Thromboembolism, hypertension, ische- include thromboses, increase of the blood mic heart disease, diabetes mellitus in a pressure, edema, headache, nausea, severe form, hormone-dependent tu- vomiting, chloasma. mours, epilepsy, neuroses, psychoses, Gestagens cause fatiguability, depress- pregnancy and lactation, progressive sion, body weight increase, libido diseases of liver and kidneys, diseases decrease, painfulness of mammary of the brain vessels, marked hyper- glands, intermenstrual bleedings lipidemia Spermicides may cause the development of vaginal dysbiosis Vaginal dysbiosis

NB! Before using contraceptives it is necessary to examine mammary glands, to check blood pressure, to determine the glucose level in urine and to check the hepatic function, to take a vagina smear test. In the case of the prolonged administration of oral contraceptives the medical examination should be taken every 6 months. The administration of contraceptives should be stopped three months before a planned pregnancy.

The pharmacological “face” of contraceptives

Medicines The peculiarities of Other indications contraception For women: Ovidon With the phenotype of the Dysfunctions of the menstrual estrogen character cycle Logest Over 35 years old, after Dysfunctions of the menstrual abortion, with cycle + juvenile uterine hyperandrogenisation bleedings Antiovin With the phenotype of the gestagen character Dysfunctions of the menstrual Tri-regol Young women, adolescents cycle Triquilar Levonorgestrel In lactation, irregular sexual life (high doses); concomitant diabetes mellitus, hypertension, obesity (mini-pills) Benzalkonium Any age, in irregular sexual life Prevention of some sexually chloride transmitted diseases, endometriosis

138 The list of medicines INN, (Trade name) Medicinal form, dosage Antiovin Tabl. № 21 Benzalkonium chloride (Farmatex, Erotex) Vaginal cream 2% Levonorgestrel (Postinor) Tabl. 0.00075 Linestrenol (Exlutone) Tabl. 0.00075 Logest Tabl. №21 Ovidon Dr. №21 Tri-Regol Tabl. №21 Triquilar Dr. № 21

Glossary Ovum implantation is the introduction of the fertilized ovum into the mucous membrane of the uterus. Libido means sexual desire. Postcoital contraceptive is contraceptive used immediately after a sexual intercourse. Spermatozoon fragmentation is the destruction of spermatozoons by the medicine affection. Folliculogenesis is the process of the follicle’s maturation. Chloasma is the skin hyperpigmentation in the form of yellowish-and-brownish patches.

MEDICINES AFFECTING MYOMETRIUM These medicines are the medicinal agents that increase (uterotonics) or decrease (tocolytics) the uterine tone and contractions.

Classification of medicines Uterotonics Uterolytics (tocolytics) Oxytocin Dinoprost Estron Fenoterol Salbutamol Ergotal Pachycarpine hydroiodide Progesterone

Uterotonics

The mechanism of action The mechanism of action of Oxytocin is connected with the stimulation of oxytocin receptors of the uterine smooth muscle cells, which leads to the increase of the calcium level in a cell and intensification of the uterine contractions. Being progesterone antagonist Dinoprost stimulates prostaglandin receptors of the myometrium cell membranes and intensifies the uterine contractions. Pachycarpine hydroiodide increases the sensitivity of the M-cholinoreceptors of the uterus to endogenous acetylcholine, as a result the uterine contractility intensifies. Ergotal stimulates α1-adrenoreceptors of the uterus and it leads to the increase of its tone. Estron increases the sensitivity of the uterus (in the end of pregnancy) to endogenous stimulators: oxytocin and prostaglandins.

Pharmacodynamics (effects) → Indications Uterotonic effect Labour induction, hypotonic uterine bleedings Side effects → Contraindications Myometrium hypertone Pregnancy

139 Tocolytics The mechanism of action Fenoterol, Salbutamol stimulate inhibitory β2-adrenoreceptors of the uterus and it leads to its relaxation. Progesterone decreases the sensitivity of the myometrium to endogenous oxytocin.

Pharmacodynamics (effects) → Indications Tocolytic effect Threatened preterm labour Side effects → Contraindications

β2-adrenomimetics – tachycardia, Arrhythmias, hypotension, diabetes blood pressure decrease, hyperglycemia mellitus Gestagens – hypertension, thromboses Hypertension, predisposition to thrombosis

The pharmacological “face” of medicines affecting the myometrium UTEROTONICS Medicines affecting primarily on The action in: Belong to the uterine: group of tone contractility labour stopping bleedings Oxytocin ++ +++ ++++ + hormones of the hypophysis posterior lobe Dinoprost + ++ +++ - analogues of prostaglandins Estron + ++ + - estrogens Ergotal +++ - - ++ Claviceps purpurea alkaloids Pachycarpine + ++ ++ - Ganglionic blockers TOCOLYTICS Belong to the group of Other effects Fenoterol β2-adrenomimetics Broncholytic Salbutamol Progesterone gestagens Gestagenic

The list of medicines INN, (Trade name) Medicinal form, dosage Dinoprost (Prostine F2α) Sol. for inj. 0.5% Ergotal Sol for inj. 0.05% Estron (Folliculin) Sol for inj. 0.1% Fenoterol (Berotec, Partusystene) Aerosol 0.1 mg/1dose Oxytocin Sol. for inj. 10 U/ml Pachycarpine hydroiodide Sol. for inj. 3% Progesterone Caps. 0.1

140 Salbutamol (Ventoline) Sol. for inj. 0.1%; tabl. 0.002

Glossary Tocolytic (uterolytic) effect is decrease of the uterine tone and contractility. Uterotonic effect is intensification of the uterine tone and contractility.

XIV. ANTIMICROBIAL, ANTIVIRAL AND MEDICINES

ANTISEPTICS AND DISINFECTANTS

Antiseptics are antimicrobial medicines, which disturb the normal course of biochemical processes in microbes due to inhibition of the enzymatic systems activity and have mainly bacteriostatic type of action. Antiseptics act selectively to certain types of microorganisms. Disinfectants are medicines, which cause irreversible changes in the protoplasm of microbial cells and lead to their rapid death, i.e. they have bactericidal type of action. They do not have a marked selective action to microorganisms.

Classification of medicines Haloids Oxidants Alkalies Salts of heavy Acids metals Chloramine B Hydrogen Sodium Mercury Salicylic acid peroxide tetraborate dichloride Benzoic acid Povidone- Potassium Silver nitrate iodine permanganate Dyes Nitrofurans Derivatives of Aldehydes and 8-oxyquinoline Brilliant green Nitrofural Nitroxoline Tricresol Methylene Furadonine Hexamethylen- blue tetramine Ethanol Tars and resins Antibacterial Detergents medicines of natural origin Ichthammol Novoimanine Ethonium Medical ozokerite Chlorophyllipt Decamethoxine Ectericide Miramistine

The mechanism of action They cause the protein coagulation in microbes, alter the permeability of their cell wall, inhibit the enzymatic activity.

Pharmacodynamics (effects) → Indications Antiseptic, bacteriostatic Treatment of wounds, burns, ulcers, disinfection of the operational field and syringes, washings in gynecology, urology, stomatology Disinfectant, bactericidal Disinfection of hands and instruments, sterilization of instruments, patient’s ejecta and excrements, premises, furniture and clothes

141 The list of medicines

INN, (Trade name) Medicinal form, dosage Benzoic acid Pwd. Brilliant green Sol. 1; 2% Chloramine B Pwd. 10.0 Chlorhexidine Pwd. Chlorophyllipt Sol. 1% Decamethoxine (Septefril) Tabl. 0.1, sol. 0.02% Ectericide Sol. 250 ml Ethanol Sol. 70%, 96% Ethonium (Ethonium ointment) Ointment 1% Formaldehyde (Formalin) Sol. 100 ml Furadonine Tabl. 0.05 Hexamethylentetramine Sol. for inj. 40%, tabl. 0.5 Sol. 3% Ichthammol Ointment 100.0 Medical ozokerite Bars 2 kg Mercury dichloride Tabl. 0.5 Sol. 1% Miramistine Sol. 0.01% Nitroxoline (5-NOC) Tabl. 0.05 Nitrofural (Furacilin) Tabl. 0.1, ointment 0.2% Novoimanine Sol. 1% Phenol (Carbolic acid) Sol. 10, 15, 25 ml Potassium permanganate Pwd. 15.0 Povidone iodine (Betadine, Polyiodine) Sol. 10% Salicylic acid Sol. 1% Silver nitrate Pwd. Sodium tetraborate (Bura) Sol. 20% Tricresol Sol. 2.5%

Glossary Bacteriostatic type of action is the action directed to inhibition of the growth and reproduction of microorganisms. Bactericidal type of action is the action leading to the rapid death of microorganisms.

ANTIBIOTICS

Antibiotics are substances of biological origin synthesized by microorganisms or isolated from plant and animal tissues, as well as their semi- synthetic and synthetic analogues selectively suppressing the viability of microorganisms sensitive to them.

142

Classification of antibiotics

Antibiotics are classified according to the origin, chemical structure, mechanism (fig. 5) and peculiarities of their action (type and spectrum) to microorganisms. By the chemical structure antibiotics are divided into: - β-lactams (with the β-lactam ring in the structure: , cephalosporins, monobactams, carbapenems); tetracyclines (with four condensed six-membered heterocycles in the structure); macrolides and azalides (with the macrocyclic lactone ring in the structure); aminoglycosides (containing aminosugars in the molecule); lincosamides, chloramphenicols (derivatives of dioxyaminophenylpropane); rifamycines, polymyxines (cyclic polypeptides); fusidines, glycopeptides, antibiotics of other chemical groups.

Classification of antibiotics by the mechanism and type of action

Bactericidal Bacteriostatic

Disturbing the synthesis of the structure the protein the protein synthesis at the microbial cell and function synthesis at the the ribosome level wall components of the level of (reversibly) cytoplasmatic ribosomes* membrane (irreversibly), nucleic acids β-lactams Polymyxines Aminoglycosides* Macrolides Glycopeptides Gramicidine Rifamycines Azalides Phosphomycine Antimycotic Fluoroquinolones Oxazolidinones Cycloserin antibiotics Griseofulvin Fusidines Lincosamides Tetracyclines Fusidines Chloramphenicols

 they are not classical antibiotics, but they are synthetic antimicrobial medicines that are close to antibiotics in their pharmacological properties.

There are also antitumour antibiotics. By the spectrum of the antibacterial action, antibiotics can be of wide (broad), moderate and narrow spectrum of action. Antibiotics of the wide spectrum of action are prescribed in the case of severe course of disease, before obtaining the results of the antibiogram and in mixed infections. When determining the causative agent of the disease it is expedient to use antibiotics with the narrow spectrum.

143

Fig. 5. The main mechanisms of the antibiotics antimicrobial action

By the type of the antibacterial action there are antibiotics with the bacteriostatic and bactericidal (they have a fast therapeutic effect in severe infections, their use is rarely accompanied by recurrences of the disease and the cases of bacteria-carrying) action. Antibiotics with the bacteriostatic type of action are rather effective for diseases of the average severity and in the cases of the prolonged treatment of the patient. There are antibiotics of the first and the second therapy line. Medicines of the second line are less active than the first line medicines and they are prescribed in the case when medicines of the first line are non-effective or when the strain of the pathogen isolated is more sensitive to these medicines. There is also a separate group of reserve medicines that are prescribed only in special cases when the Ist and the IInd line medicines are not effective.

Typical side effects of therapy

Resistance of microorganisms to antibiotics. Superinfection is development of a new infection following the previous unfinished infectious process, especially when caused by microorganisms that are resistant or have become resistant to the antibiotics used earlier. Dysbacteriosis (dysbiosis) is suppression of the normal microflora of macroorganism accompanied by reproduction of conditionally pathogenic microorganisms that are previously either absent or present in insufficient amounts in the organism and suppressed by the normal microflora. Allergic reactions are typical for most antibiotics. There may be an immediate (acute), as well as delayed type responses.

144 The main principles of the rational antibiotic therapy

1. Antibiotics should be prescribed only taking into account the type of causative agent isolated and antibiogram. Choose the most active and the least toxic medicine. 2. Determine the optimal doses of antibiotics and their scheme of administration taking into consideration the drug pharmacokinetics, the severity of the disease, the condition of the liver and kidneys, as well as the age of the patient. 3. The concentration of the antibiotics should exceed the minimal inhibiting concentration for the pathogen isolated 3-4 times. 4. Take into account side effects of the antibiotics, especially in the case of hepatic and renal insufficiency. 5. Determine the presence of hypersensitivity of a patient to the definite antibiotic. 6. Begin the treatment timely and take the whole course of the antibiotic treatment. 7. Take into account a cross-sensitivity to antibiotics. Combine antibiotics of different groups to broaden the spectrum of their action and to enhance their antibacterial effect. 8. Prescribe concomitantly antifungal agents to prevent dysbacteriosis.

Antibiotics of the β-lactam structure

The group of β-lactam antibiotics includes medicines of the following groups: penicillins, cephalosporins, carbopenems and monobactams. All these groups of antibiotics contain the β-lactam ring, which determines their antimicrobial activity, in the nucleus of the molecule. β-lactam antibiotics differ from each other by their resistance to hydrochloric acid of the gastric juice and it determines the route of their administration. Natural penicillins (excluding phenoxymethylpenicillin), anti-pseudomonal penicillins, most of cephalosporins, as well as carbopenems, monobactams are decomposed in the stomach and are administered only parenterally. β-lactam antibiotics are evenly distributed in an organism accumulating therapeutic concentrations in many organs, tissues and biological fluids. Crossed allergic reactions between penicillins and other β-lactam antibiotics are observed.

The mechanism of action The mechanism of action of all β-lactam antibiotics is similar. It is based on the inactivation of enzymes that participate in the synthesis of peptidoglycan mureine, the main component of the external membrane (cell wall) of microorganisms, and it leads to the death of the microbial cell.

Penicillins Peculiarities of penicillins 1. The greatest effect on gram-positive (G+) microorganisms, which cellular wall contains from 40 to 90% of peptidoglycans (gram-negative (G-) ones – only 5%). 2. The effect only to divisible cells because the growing microbial cells need the material to build the cellular wall. 3. A low toxicity. 4.A broad spectrum of the therapeutic action. 5. A good absorption, distribution and penetration into tissues.

145 Classification of medicines Natural Short-acting Depo-medicines Sodium and potassium salts of Bicillin-5 Semi-synthetic Antistaphylococcal Aminopenicillins Antipseudomonal Combined  Oxacillin . Ampicillin Carbenicillin . Amoxiclav . Cloxacillin . Amoxicillin Azlocillin (Amoxicillin+ clavulanic acid) . Helicocin (Amoxicillin+ Metronidazole)  -resistant to β-lactamases, ▪ -acid resistant

Pharmacodynamics (effects) → Indications Antibacterial effect. Rheumatism, syphilis, angina, The type of action is bactericidal. pneumonia, meningitis, abscess, otitis, The spectrum of action is moderate diphtheria, gas gangrene, peptic ulcer, (natural penicillins) and broad (semi- anthrax synthetic penicillins), including G+ and G- cocci, G+ bacilli, anaerobes, spirochetes Side effects → Contraindications Neurotoxicity (tremor, Epilepsy (especially in endolumbal convulsions, hallucinations), administration). High doses during pregnancy bleeding should be administered with care

Antipseudomonal penicillins have a broader antibacterial spectrum comparing to other penicillins. The spectrum of action of semi-synthetic penicillins considerably expands (they are active against such G- microorganisms as Klebsiella, Proteus vulgaris, anaerobes, bacteroids) due to their combination with inhibitors of β- lactamases, i.e. clavulanic acid, sulbactam and tazobactam. The simultaneous administration of penicillins with bacteriostatic antibiotics and sulphonamides should be avoided since they decrease the efficiency of penicillins. Penicillinase is administered as an antidote in poisoning (allergy) by penicillins.

The list of medicines INN, (Trade name) Medicinal form, dosage Azlocillin (Securopen) Pwd. for inj. 1.0 Amoxiclav ( Amoxicillin + clavulanic acid) Tabl. 0.625 Amoxicillin (Quiconcil) Tabl. 0.5 Ampicillin (Ampicillin trihydrate) Tabl. 0.5, pwd. for inj. 0.5 Benzylpenicillin sodium and potassium salts Pwd. for inj. 1000000 U () Bicillin-5 Pwd. for inj. 1500000 U Carbenicillin Pwd. for inj. 1.0

146 Cloxacillin (Cloxapen) Tabl. 0.5, pwd. for inj. 0.5 Oxacillin (sodium salt of oxacillin) Tabl. 0.5, pwd. for inj. 0.5 Helicocin (Amoxicillin + Metronidazole) Tabl. № 36

Cephalosporins

The group of cephalosporins is the class of natural and semi-synthetic β- lactam antibiotics, which contain 7-aminocephalosporanic acid (7-ACA).

Classification of medicines

The Ist The IInd The IIIrd The IVth generation generation generation generation Cephazolin Cefuroxime Cephtriaxone Cephepim . Cephalexin . Cephaclor . Cephixim Cephpirom . acid resistant

Peculiarities of cephalosporins 1. Close to penicillins in their structure and pharmacological properties. 2. A low toxicity and a good pharmacokinetics. 3. A good combinability with other antibacterial agents. 4. A high resistance to the affection of Staphylococcal β-lactamases comparing to penicillins. Cephalosporins of different generations differ in the spectrum of their antibacterial action (table 5).

Table 5. Generation of Effectiveness against cephalosporins Gram-positive bacteria Gram-negative bacteria The first +++ +/- The second ++ + The third + +++ The fourth ++ +++

Pharmacodynamics (effects) → Indications Antibacterial effect. Infections of respiratory tract, skin and soft tissues, The type of action is bones and joints, urinary tract, heart; prevention of bactericidal. infections after surgery. Meningitis and blue pus The spectrum of action is (pseudomonal) infection –cephalosporins of the III- broad IV generations Side effects → Contraindications Bleeding, hemato-, nephro-, , epilepsy, severe disorders of kidneys and neuro-, hepatotoxicity liver functions, pregnancy, lactation

The list of medicines INN, (Trade name) Medicinal form, dosage Cefuroxime (Zinaceph, Zinnat) Pwd. for inj. 0.5 Cephazolin (Kefzol, Reflin) Pwd. for inj. 0.5 Cephaclor (Ceclor) Caps. 0.5

147 Cephalexin Caps. 0.5 Cephepim (Maxipim) Pwd. for inj. 0.5 Cephixim Caps. 0.1 Cephpirom (Keyten) Pwd. for inj. 0.5 Cephtriaxone (Longaceph) Pwd. for inj. 0.5

Carbapenems and monobactams

The peculiarity of these classes of antibiotics is the fact that their structure is based on the simple β-lactam ring, which is not bound to a thiazolidine ring in contrast to penicillins and cephalosporins.

Classification of medicines Carbapenems Monobactams  -cylastatin  Aztreonam  Meropenem*  – resistant to β–lactamases * resistant to renal dehydropeptidase-1

Carbapenems Peculiarities of carbapenems

1. A marked resistance to the affection of β-lactamases. 2. A slow development of microorganisms resistance (exceptions are blue pus bacilli and staphylococci). 3. A super broad spectrum of action. 4. Strong post-antibiotic effect. 5. Antibiotics of a super deep reserve (second choice)! 6. Antibiotics have relatively low toxicity and are well-tolerated.

Pharmacodynamics (effects) → Indications Antibacterial effect. Severe hospital infections caused by a The type of action is bactericidal. multi-resistant strains of microor- The spectrum of action is extremely ganisms; infections of bones and joints, broad covering the majority of aerobic and skin and soft tissues, abdominal cavity, anaerobic G+ and G- bacteria. Chlamydia, female reproductive organs, urinary mycoplasmas, tuberculous and leprosy tract; bacterial endocarditis (imi- mycobacteria, pseudomonads (except blue penem), pneumonia, septicemia, me- pus bacillus) have a natural resistance to ningitis (meropenem) carbapenems Side effects → Contraindications Hemato-, neurotoxicity Blood disorders, epilepsy, pregnancy, lactation

Imipenem is metabolized in the epithelium of renal tubules by renal dehydropeptidase-1 with the formation of nephrotoxic metabolites. To prevent this process imipenem is co-administered with cylastatin, an inhibitor of the enzyme, in the ratio of 1:1. A combined medicine imipenem-cylastatin has a trade name Tienam.

148 Monobactams Peculiarities of monobactams 1. A second choice group. 2. A high resistance to the affection of β-lactamases of the gram-negative flora. 3. The absence of the cross-sensitive allergy with penicillins and cephalosporins. 4. A slow development of microorganisms’ resistance. 5. A possible use for newborns treatment.

Pharmacodynamics (effects) → Indications Antibacterial effect. Severe infections of different location The type of action is bactericidal. caused by gram-negative flora that is The spectrum of action is narrow (G- resistant to the 3rd generation of aerobes, gonococci, meningococci, cephalosporins, to the 2nd and 3rd Salmonellas, Shigellas, Klebsiellas, generations of aminoglycosides, and Proteus, E. coli and blue pus bacilli) antipseudomonal penicillins Side effects → Contraindications Bleeding, hepatotoxicity Bleeding, dysfunctions of the liver and kidneys. They should be used carefully in pregnancy and lactation

The list of medicines INN, (Trade name) Medicinal form, dosage Aztreonam (Azactam) Pwd. for inj. 0.5 Imipenem-cylastatin (Tienam) Pwd. for inj. 0.5 Meropenem (Meronem) Pwd. for inj. 0.5

Glossary Anaerobes are microorganisms that are capable to exist without oxygen. Aerobes are microorganisms that need free oxygen to survive. Meningitis is the inflammation of brain and spinal cord membranes. Post-antibiotic effect is a phenomenon of the antibacterial effect presence after discontinuation of the antibiotics’ administration. Erysipelas is an infectious and inflammatory disease of the skin and soft tissues often caused by streptococci. The spectrum of action is the list of microorganisms that are sensitive to a medicine. β-lactamases are enzymes of microorganisms produced for protection and that destroy a β-lactam ring of antibiotics.

Tetracyclines The group of tetracyclines includes natural and semi-synthetic antibiotics. Their chemical structure is based on 4 condensed six-membered rings.

Classification of medicines

Natural Semi-synthetic Tetracycline Methacycline Doxycycline

By duration of their effect tetracyclines are divided into short-acting medicines (6-8 hours and they are administered 4 times per 24 hours) – tetracycline; long-acting

149 ones (12-24 hours and they are administered 1-2 times per 24 hours) – methacycline, doxycycline.

Peculiarities of tetracyclines 1. The bacteriostatic type of action. 2. A broad spectrum of antibacterial activity, but a high level of secondary resistance of many bacteria. 3. A good absorption from the gastrointestinal tract. 4. Frequent side effects.

The mechanism of action They bind to 30S-subunit of bacterial ribosomes and it prevents inclusion of aminoacids into the protein peptide chains (only in the phase of microorganisms active growth), i.e. it disturbs the protein synthesis.

Pharmacodynamics (effects) → Indications Antibacterial effect. Infections of respiratory tract, The type of action is bacteriostatic. biliary tract, abdominal and The spectrum of action is broad (including G+ intestinal infections, syphilis, and G- cocci, bacilli, intracellular pathogens, Helicobacter pylori eradication anaerobes). Side effects → Contraindications Dysbiosis, dyspepsia, decrease of the body weight, Severe diseases of the liver hepato-, hemato-, nephro-, neurotoxicity, muto- and and kidneys, pregnancy, teratogenecity, photodermatitis, growth disorder of lactation, myasthenia, age bones and teeth under 8

Food and antacids reduce bioavailability of tetracyclines considerably because of their formation of poor soluble chelate complexes with aluminium, calcium, magnesium. That is why these medicines should be taken on an empty stomach an hour before meals or two hours after meals. They should not be taken with milk.

The list of medicines INN, (Trade name) Medicinal form, dosage Doxycycline (Vibramycine) Caps. 0.1, sol. for inj. 2% Methacycline (Rondomycine) Caps. 0.3 Tetracyline (Imex) Caps. 0.12, oint. 3%

Glossary Helicobacter pylori is a Gram-negative bacterium causing development of peptic ulcer. Photodermatitis is allergic skin disease caused by hypersensitivity to the sun light.

Macrolides and azalides

It is a group of antibiotics containing a macrocycle lactone ring bound to carbohydrate part.

150 Classification of medicines

Macrolides and azalides* The Ist The IInd The IIIrd Combinations of generation generation generation macrolides with tetracylines and other* medicines Erythromycine Roxythromycine Azythromycine* Oletetrin Clarythromycine Zynerit*

A group of azalides is close to macrolides group, they are sometimes considered as the IIIrd generation of macrolides.

Peculiarities of macrolides 1. The bacteriostatic action with the primary activity to G+ (streptococci, staphylococci) microorganisms. 2. Activity against intracellular microorganisms (Chlamydia, mycoplasmas, legionellas). 3. One of the least toxic antibiotics. 4. A good absorption from the gastrointestinal tract. 5. Capable to accumulate in the site of inflammation.

The mechanism of action They bind to ribosomes of microorganisms, inhibit the RNA synthesis and the protein synthesis in the microbial cell. Thus, the growth and reproduction of microorganisms are blocked.

Pharmacodynamics (effects) → Indications Antibacterial effect. Infections of respiratory, urinary, biliary The type of action is bacteriostatic. tract; reproductive system; diphtheria, The spectrum of action is broad syphilis, skin infections (including G+, G—cocci, intracellular microorganisms) Side effects → Contraindications Seldom: hepatotoxicity, photo- Dysfunctions of the liver, kidneys, heart dermatitis, arrhythmias

The list of medicines

INN, (Trade name) Medicinal form, dosage Azythromycine (Sumamed) Caps. 0.25 Clarythromycine (Clacid) Tabl. 0.5 Erythromycine (Meromycine) Tabl. 0.1, oint. 2% Oletetrin Caps. 0.25 Roxythromycine (Rulid) Tabl. 0.1 Zinerit (Erythromycine + acetate) Pwd. 30.0

151 Aminoglycosides Aminoglycosides are antibiotics of оligosaccharide structure.

Classification of medicines Aminoglycosides (AG) The Ist and IInd* generation The IIIrd generation Streptomycine Neomycine Amycacine Tobramycine Gentamycine* Canamycine Peculiarities of aminoglycosides 1. A broad spectrum of action and a powerful bactericidal effect, especially on G- microflora. 2. A high toxicity, but rare allergic reactions. 3. Medicines of the IInd and the IIIrd generations potentiate the effect of penicillins and cephalosporins.

The mechanism of action Aminoglycosides suppress the protein synthesis in the microbial cell irreversibly as the result of binding to ribosomes. Pharmacodynamics (effects) → Indications Antibacterial effect. Hospital infections; sepsis, peritonitis, The type of action is bactericidal. endocarditis, pneumonia, infections of The spectrum of action is broad small pelvis organs (pyelonephritis, (including aerobes, G- microflora: E. urosepsis), osteomyelitis, meningitis of the coli, Proteus, Salmonellas, Klebsiella, unclear etiology Enterobacter, Shigellas). Medicines of the IInd and the IIIrd generations affect blue pus bacillus

Side effects → Contraindications Nephro-, oto-, neurotoxicity Dysfunction of the kidneys, hearing and vestibular apparatus disorder, the CNS diseases, concomitant administration of muscle relaxants The list of medicines INN, (Trade name) Medicinal form, dosage Amycacine (Amycine) Sol. for inj. 5 % Gentamycine (Garamycine) Sol. for inj. 1; 4 % Canamycine Sol. for inj. 5 % Neomycine Ointment 2 % Streptomycine Pwd. for inj. 0.5 Тоbramycine Sol. for inj. 1; 4 % Glossary Osteomyelitis is the inflammation of the bone marrow and relating bone tissue. Sepsis is a severe disease caused by continuous or periodical coming of microorganisms into the blood.

152 Glycopeptides Medicines Vancomycine Teicoplanine

Peculiarities of glycopeptides 1. Highly active against G+ microflora, especially to methycillin-resistant staphylococci and enterococci. 2. The bactericidal type of action. 3. A slow development of microbes resistance and the absence of cross resistance with all other antibiotics.

The mechanism of action Like -lactam antibiotics, glycopeptides suppress the synthesis of the cellular wall peptidoglycane.

Pharmacodynamics (effects) → Indications Antibacterial effect. Severe hospital infections caused by resistant The type of action is bactericidal. strains of staphylococci; enterococci, The spectrum of action is broad streptococci resistant to penicillins; sepsis, (including G + aerobic and pneumonia, meningitis, endocarditis, infections anaerobic microorganisms: strepto- of the skin and soft tissues, bones and joints, cocci, pneumococci, enterococci) pseudomembranous colitis Side effects → Contraindications Nephrotoxicity Dysfunction of the kidneys Ototoxicity Hearing disorders Syndrome of "a red person‖ Allergic reactions

The list of medicines INN, (Trade name) Medicinal form, dosage Teicoplanine (Targocide) Pwd. for inj. 0.2 Vancomycine (Vancocine) Pwd. for inj. 0.5

Glossary Syndrome of "a red person" is a syndrome accompanied by the rush of blood (and redness) to the face, neck, BP decrease, pain in the chest and back, dyspnea, rash (because of release of a great amount of histamine). This syndrome appears with a fast intravenous injection of glycopeptides.

ANTIBIOTICS OF DIFFERENT GROUPS

Classification of medicines Lincosamides Fusidines Chloramphenicols Rifamycines Lincomycine Fusidic acid Chloramphenicol Rifampicine hydrochloride Levosin Levomecol Phosphomycines Polymyxines Oxazolidinones* and others Phosphomycine Polymyxine B sulphate Linezolide * Fusafungin Gramicidine

153 The mechanism of action Lincosamides, fusidic acid, chloramphenicols, oxazolidinones disturb the synthesis of bacterial proteins; rifamycine inhibits the synthesis of RNA; phosphomycines break the formation of a cellular wall. Polymyxines and gramicidine break the structure and function of cytoplasmatic membranes. Fusafungin suppresses colonization and adhesion of microorganisms on the mucous membrane of the upper respiratory tract. Lincosamides Pharmacodynamics (effects) → Indications Antibacterial effect. Reserve antibiotics in treatment severe The type of action is bactericidal and staphylococcal, streptococcal, аnaerobic bacteriostatic. infections The spectrum of action is broad (including G+ microorganisms, anaerobes) Side effects → Contraindications Dyspepsia, pseudomembranous colitis. Colitis. Liver diseases. Leukopenia, Hepatotoxicity. Leukopenia, neutropenia, neutropenia, thrombocytopenia thrombocytopenia

Chloramphenicols Pharmacodynamics (effects) → Indications Antibacterial effect. Infections of the GIT, meningitis, gas The type of action is bacteriostatic. gangrene, plague, rickettsioses, typhoid, The spectrum of action is broad (including abdominal and pelvis infections G+ microorganisms, anaerobes) Side effects → Contraindications Accumulation in the bone marrow. Pregnancy, lactation, children under 10, anaemias, Inhibition of blood formation leukopenia, HIV-infection Fusidines Pharmacodynamics (effects) → Indications Antibacterial effect. Staphylococcal infections when The type of action is bacteriostatic. staphylococci are resistant to other The spectrum of action is narrow antibiotics and if there is allergy to - (staphylococci, anaerobes) lactams Side effects → Contraindications Dyspepsia Diseases of the GIT Oxazolidinones Pharmacodynamics (effects) → Indications Antibacterial effect. The type of action is bacteriostatic. Pneumonia, endocarditis, The spectrum of action is broad (including G+ aerobes, severe infections caused by anaerobes, resistant to other antiobiotics) enterococci Side effects → Contraindications Anaemia, thrombophlebitis Pregnancy, lactation Increase of bilirubin level Liver diseases

154 Polymyxines Pharmacodynamics (effects) → Indications Antibacterial effect. Severe G- infections caused by multi- The type of action is bactericidal. resistant hospital strains of The spectrum of action is narrow (G- microorganisms bacteria, including Salmonellas, cholera vibrion, blue pus bacillus) Side effects → Contraindications Nephrotoxicity Hepatic insufficiency Neurotoxicity Myasthenia, pregnancy, children under 12, administration of muscle relaxants NB! Polymyxines are used only by vital indications because of their toxicity.

Rifamycines Pharmacodynamics (effects) → Indications Antibacterial effect. Tuberculosis, leprosy, pneumonia, The type of action is bactericidal. infections of urinary and biliary tract, The spectrum of action is broad osteomyelitis, meningitis (including G- microorganisms, chlamydia, tuberculous mycobacteria) Side effects → Contraindications Hepato-, hematotoxicity Liver diseases. Pregnancy, age under 1 year old

Phosphomycines Pharmacodynamics (effects) → Indications Antibacterial effect. Acute non-complicated infections The type of action is bactericidal. of urinary and biliary tract, sepsis, The spectrum of action is broad (including G- meningitis microorganisms) Side effects → Contraindications Dyspepsia Children under 5

Gramicidine Pharmacodynamics (effects) → Indications Antibacterial effect. Purulent inflammatory processes of the The type of action is bactericidal. skin and mucous membranes The spectrum of action is moderate (including G- microorganisms) Side effects → Contraindications Contact dermatitis Dermatitis

Fusafungin Pharmacodynamics (effects) → Indications Antibacterial effect. Infections of the upper The type of action is bacteriostatic. respiratory tract

155 The spectrum of action is broad (including G+ and G- microorganisms, anaerobes) Side effects → Contraindications Nasopharynx irritation, laryngo-, Children under 2.5 years old, bronchospasm laryngospasm

Comparison of the pharmacological “face” of antibiotics of different groups Medicines Spect- Type of Resistance Toxi- Peculiarities of rum action city action Lincosamides B Bs, bc slowly ++ Accumulation in bones and joints Polymyxine B N (G-) Bc -//- ++++ It is not absorbed sulphate from the GIT Gramicidine M Bc no +++ Only local admi- nistration Chloramphenicol B Bs -//- ++++ GIT infections. Reserve A! Fusidines N Bs rapidly ++ Reserve A! 90% of bioavailability Rifamycine B Bc rapidly ++ Microsomal enzymes inductor. It is effective in TB Phosphomycines B Bc slowly ++ Infections of urinary G+

The list of medicines INN, (Trade name) Medicinal form, dosage Chloramphenicol (Levomycetine) Tabl. 0.5, sol. 3 % Fusafungin (Bioparox) Aerosol 0.125 mg/dose Fusidic acid Tabl. 0.25, sol. 1 % Gramicidine Oint. 4 % Levomecol Oint. 30.0 Levosin Oint. 40.0 Linezolide (Zyvox) Tabl. 0.6, sol. for inj. 0.2 % Lincomycine hydrochloride Caps. 0.5, sol. for inj. 30 % Phosphomycine Pwd. 3.0 Polymyxine B sulphate (Polymyxine B) Pwd. for inj. 0.05 Rifampicine (Rifadine) Tabl. 0.6, caps. 0.6, syrup 2 %

156 Glossary Сolitis is an inflammatory disease of large intestine. Rickettsiosis is a disease caused by Rickettsiae (G- microorganisms).

FLUOROQUINOLONES By the chemical structure fluoroquinolones are synthetic antibacterial medicines, derivatives of quinolone, containing fluorine atoms in their structure. Nowadays fluoroquinolones are considered to be a serious alternative to highly active antibiotics of the broad spectrum of action when treating severe infections.

Classification of medicines The Ist generation The IInd generation The Шrd generation Norfloxacine Levofloxacine Moxifloxacine Ofloxacine Sparfloxacine Cyprofloxacine

Peculiarities of the group 1. A unique mechanism of action and a strong bactericidal effect. 2. A super broad spectrum of the antibacterial action. 3. A good pharmacokinetics (a high bioavailability, the long period of elimination, all medicines are stable to acid). 4. A slow development of resistance in microorganisms. 5. The presence of the post-antibiotic effect. 6. A high efficiency in treatment infections of any location and a good tolerance in patients. 7. A possibility of application as empirical therapy in severe infections at hospital.

The mechanism of action Fluoroquinolones inhibit DNA-gyrase (topoisomerase) of bacteria and it leads to disturbance of biosynthesis of DNA, RNA, and then of protein in a microbial cell.

Pharmacodynamics (effects) → Indications Antibacterial effect. Infections of urinary and respiratory tract, The type of action is bactericidal. bones and joints, skin, soft tissues; The spectrum of action is super broad intestinal infections, sepsis; gonorrhea, (including G+ and G- aerobic and meningitis, chlamydiasis, tuberculosis anaerobic microorganisms, chlamydia, mycoplasmas, legionellas, mycobac- teria) Side effects → Contraindications Chondrotoxicity Persons under 18

157 Comparison of the pharmacological “face” of antibiotics (A) and fluoroquinolones

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Spect Type of Type Antibio P M*/B bc + - q For peptic ulcer. A cross allergy with CS CS B bc ++ +** A cross allergy with P. A high resistance to - lactamases C SB bc +++ + A high resistance to - s M N bc +++ + lactamases T B bs +++ - + q It is used for peptic ulcer ML B bs + - + For peptic ulcer. The prolonged action GP B bc +++ + n They are used for pseudomembranous colitis AG B bc ++++ +** For tuberculosis treatment F SB bc +++ + + s They have immuno- modulating effect P – penicillins, CS – cephalosporins, C – carbapenems, M – monobactams, T – tetracyclines, ML – macrolides, GP – glycopeptides; AG – aminoglycosides; F – fluoroquinolones; B – broad; N – narrow, M – moderate, SB – super broad; bc – bactericidal, bs – bacteriostatic; PAE – post-antibiotic effect; ICA – intracellular activity; s – slowly, q – quickly, n – no; * - a moderate spectrum of action for natural penicillins; ** - only medicines of the III-IV generations.

The list of medicines INN, (Trade name) Medicinal form, dosage Cyprofloxacine (Cyfran) Tabl. 0.25 Levofloxacine Tabl. 0.5 Moxifloxacine Tabl. 0.4 Norfloxacine Tabl. 0.4 Ofloxacine (Floxal) Tabl. 0.2 Sparfloxacine Tabl. 0.2

Glossary Chondrotoxicity is ability of medicines to cause pathological changes in a cartilage tissue (it is especially dangerous for children). Gonorrhea is an infectious venereal disease caused by gonococci with the primary affection of mucous membranes of urinary and genital organs. Tuberculosis is an infectious disease caused by mycobacteria with the formation of specific granulomas in tissues and organs, more often in lungs. DNA-gyrase is an enzyme, which provides superspiralisation of DNA.

158 ANTITUBERCULOUS MEDICINES These are the medicines used for specific antituberculous therapy, which inhibit the growth and development of mycobacteria or cause their death. Antituberculous medicines are divided into first-line (main) medicines, which are highly effective and have low toxicity and second-line (reserve) medicines, which are less effective and more frequently cause side effects, but which are used in case of mycobacterial resistance to first-line medicines.

Classification of medicines First-line medicines Isonicotinic acid hydrazide and para- Antibiotics and isonicotinic acid aminosalicylic acid* derivatives thioamide derivatives* Isoniazide Phthivazide Rifampicine Streptomycine sulphate Para-aminosalicylic acid (PASA)* Ethionamide* Second-line medicines Antibiotics and other drugs* Capreomycine sulphate Florimycine Ethambutol* There is also efficacy-based classification of antituberculous medicines: group A (most effective) – isoniazide, rifampicine; group B (effective) – streptomycine sulphate, ethambutol, ethionamide, cycloserine; group C (least effective) – PASA.

Mechanism of action Isonicotinic acid hydrazide and isonicotinic acid thioamide derivatives form complexes with heavy metal ions, inhibit breathing and development of tuberculosis bacilli, disturb the synthesis of mycolic acid, which is the main structural component of cell wall of given pathogen. Para-aminosalicylic acid derivatives compete with PABA, which is essential for the growth and reproduction of mycobacteria. Antibiotics inhibit synthesis of mycobacterial proteins.

Pharmacodynamics (effects) → Indications Tuberculostatic or tuberculocidal effect Tuberculosis of various forms and location Side effects → Contraindications Dyspepsia, CNS disorders Peptic ulcer, acute gastritis, erosive- ulcerous colitis; CNS diseases

Pharmacological “face” of antituberculous medicines Medicine Type of action Spectrum of action Activity Toxicity Ts Tc Broad Narrow Isoniazide + + + s +++ Phthivazide + +

159 Ethambutol + +

The list of medicines INN, (Trade name) Medicinal form, dosage Capreomycine sulphate Pwd. 1.0 Cycloserine Caps. 0.25 Ethambutol (Mycobutol) Tabl. 1.0 Ethionamide Tabl. 0.25 Florimycine Sol. for inj. 0.5 Isoniazide Sol. for inj. 10% PASA (Aminacyl) Sol. for inj. 3% Phthivazide Tabl. 0.5 Rifampicine Sol. for inj. 5% Streptomycine sulphate Pwd. 0.5

Glossary Tuberculocidal type of action is an action resulting in tuberculosis mycobacteria death. Tuberculostatic type of action is an inhibition of growth and reproduction of tuberculosis mycobacteria.

SULPHONAMIDE MEDICINES Sulphonamides are synthetic antibacterial medicines (sulphanylic acid amides) having the identical spectrum of the antimicrobial action and differing in the pharmacokinetic properties.

Classification of medicines

MONOCOMPONENT 1. Resorptive-acting (absorbed in the intestine) Short-acting Long-acting Super long-acting Sulphanylamide Sulphadimethoxine Sulphamethoxipyrazine Sulphathiazole 2. Acting in the intestine 3. Derivatives of 4. For external use (poorly absorbed from sulphonamides and 5- the GIT) aminosalicylic acid Phthalylsulphathiazole Salazosulphapyridine Sulphacetamide Silver sulphathiazole Maphenide COMBINED 1. Resorptive-acting 2. For external use (Sulphonamide+Trimethoprim) Co-trimoxazole Algimaf Streptonitol

160 The mechanism of action Sulphonamides are competitive antagonists of para-aminobenzoic acid (PABA) owing to their structural similarity. Imitating PABA sulphonamides in the certain concentration inhibit the synthesis of folic acid blocking dihydrofolate- synthetase enzyme and formation of dihydrofolic acid. Folic acid in the reduced form (tetrahydrofolic acid) participates in the synthesis of purine and pyrimidine bases that are necessary for formation of nucleic acids. As the result of disorder of the protein synthesis the process of the cellular division is slowed down, the bacteriostatic action develops. Trimethoprim breaks the folic acid metabolism blocking dihydrofolate- reductase enzyme and formation of tetrahydrofolic acid. When combining trimethoprim with sulphonamides stronger inhibition of nucleic metabolism and development of the bactericidal action take place. The silver ion binds to DNA, accumulates on the surface of the bacteria nucleus and inhibits their growth and division, and when combining with sulphonamides it provides also the bactericidal action (silver sulphathiazole).

Fig. 6. The mechanism of the sulphonamide action

Pharmacodynamics (effects) → Indications The antibacterial effect. Infectious diseases: quinsy, The type of action is bacteriostatic or bactericidal. bronchitis, pneumonia, intes- The broad spectrum of action: microorganisms that tinal infections, cystitis, synthesize the folic acid – staphylococci, strep- urethritis, prostatitis, chole- tococci, pneumococci, gonococci, meningococci, cystitis, meningitis, otitis, causative agents of intestinal infections wound infection, malaria (Salmonellas, Cholera vibrion, E.coli), chlamydias, protozoa (malarial plasmodium, toxoplasms)

161 Side effects → Contraindications Crystaluria, agranulocytosis, leukopenia; Renal insufficiency, blood formation teratogenicity disorders; pregnancy, lactation

The principles of sulphonamides dosing include the intake of loading doses followed with maintaining ones, that is connected with the mechanism of their action. Breaking the dosing principles for sulphonamide medicines (the absence of loading doses and reduction or interruption of the course of treatment) leads to development of the microorganisms strains resistant to sulphonamides. The antibacterial action of sulphonamides decreases in the presence of pus, blood, decomposed tissues where PABA and folic acid are in sufficient amount. That is why sulphonamides for external use are applied only on the preliminary cleaned wound. However, maphenide, the medicine that does not change its activity in the acid medium, is not inactivated by PABA and has the activity in an uncleaned wound. For crystaluria prevention sulphonamides should be taken with a plenty of weak alkaline drink decreasing the acidity of urine. The alkaline medium also promotes the sulphonamides transition in the ionic state and it facilitates the capture and assimilation of medicines by a microbial cell. Medicines should be taken on the empty stomach or between meals (in 2 h after the previous meal and 2 h before the following meal).

The pharmacological “face” of sulphonamides Medicines Action Absorption Bs/Bc Dose, duration strength in the GIT g/day Sulphanylamide s r +++ +/- 3-6 Sulphathiazole s +++ +/- 3-4 Phthalylsulphathiazole s + +/- 6 Sulphadimethoxine l ≥r + +/- 1 Salazosulphapyridine l + +/- 2 Sulphacetamide sl +++ +/- Silver sulphathiazole sl >r +/+ Co-trimoxazole sl >r +/+ Maphenide ** sl +/- Algimaf**(C) sl +/- Streptonitol (C) >r +/- S – short (to 8 h), l – long (8-12 h), sl – super long (24-48 h); r – reference; Bs – bacteriostatic, Bc – bactericidal, * - anti-inflammatory effect; ** - it can be used for treatment of an uncleaned wound; C – combined medicine.

The list of medicines INN, (Trade name) Medicinal form, dosage Algimaf Gel Co-trimoxazole (Bactrim, Biseptol) Tabl. 0.48, syrup 48 mg/ml Maphenide Ointment 10 % Phthalylsulphathiazole (Ftalazole) Tabl. 0.5 Salazosulphapyridine (Sulphasalazine) Tabl. 0.5

162 Silver sulphathiazole (Argosulphan) Cream 2% Streptonitol Ointment 15.0 Sulphacetamide (Sodium sulphacyl, Albucide) Sol. 30%, ointment 30% Sulphadimethoxine Tabl. 0.5 Sulphamethoxipyrazine (Sulphalen) Tabl. 0.2 Sulphanylamide (Streptocide) Tabl. 0.5, ointment 10% Sulphathiazole (Norsulphazole) Tabl. 0.5

Glossary Crystaluria is formation of crystals of insoluble acetylated derivatives of sulphonamides in kidneys with the further risk of stones formation (nephrolithiasis).

ANTIMALARIAL MEDICINES

Antimalarial (malariacidal) medicines is a group of antiprotozoal medicines used for prevention and treatment of malaria. Malaria is collective name for the group of infections of the protozoal etiology. The cyclic course with changing the periods of acute fever attacks and interictal states (recurrences and remissions), splenohepatomegalia, anaemia, severe damage of the nervous system and other organs is characteristic for malaria. The causative agent (pathogen) of malaria is malarial plasmodium (P.), a representative of protozoa. Depending on the type of plasmodium, which causes the disease, and different time of the internal erythrocytic cycle of its development malaria can be defined as three days malaria caused by P.vivax and P. ovale, four days malaria caused by P. malariae and tropical one caused by P. falciparum. Any type of plasmodia has two cycles of development: asexual reproduction (schizogony) - in the human organism and sexual one (sporogony)- in the body of a female mosquito of the Anophales genus.

Classification of medicines Medicines acting on schizogony Medicines (schizontocides, schizontotropic) acting on Combined Affecting the tissue Affecting the sporogony medicines cycle (in the liver) erythrocytic cycle (in (gamontocides, (histoschizontocides) erythrocytes) gamontotropic) (hematoschizontocides) Pyrimethamine Pyrimethamine Pyrimethamine Fansidar Proquanyl h/chl. Proquanyl h/chl. Proquanyl h/chl. (Pyrimethamine + Quinocide Chloroquine Quinocide sulphadoxine) Fansidar Mefloquine Mefloquine Fansidar

The mechanism of action The main link in the mechanism of action of antimalarial medicines is disturbance of the nucleic acids synthesis and functions of the plasmodia.

Pharmacodynamics (effects) → Indications Antimalarial effect Treatment and prevention of malaria

163 Side effects → Contraindications Hepato- and nephrotoxicity Diseases of the liver and kidneys Teratogenicity Pregnancy (especially the 1st trimester)

Antimalarial medicines have their own peculiarities in usage. So, hematoschizontocides are used for stopping acute attacks of malaria and for treatment in the case of the chronic course of the disease. Histoschizontocides are taken for chemoprophylaxis of malaria recurrences. Gamontotropics (sporocides) are medicines for the total or epidemiological prevention of malaria. When malarial plasmodia are stable to the main antimalarial medicines these medicines are prescribed in combination with sulphonamides or sulphones and it allows reducing their dose and the toxic effects, as well as increasing their efficiency.

The pharmacological “face” of antimalarial medicines Medicines Resis- Acti- The rate Accu- Other indications tance vity of the mula- deve- effect’s tion Protozoal Non-infectious lopment deve- infections diseases lopment Pyrimethamine rapidly >Q* + + Toxo- plasmosis Proquanyl rapidly ++ no Quinocide >Q Chloroquine slow >Q ++ ++ RA, SLE, TA Mefloquine + ++ *-activity relating to the reference medicine of the group – (Q), RA - rheumatoid arthritis, SLE - systemic lupus erythematosus, TA – tachyarrhythmia.

The list of medicines INN, (Trade name) Medicinal form, dosage Chloroquine (Delagil, Quingamine) Tabl. 0.25, sol. for inj. 5% Fansidar (Pyrimethamine + sulphadoxine) Tabl., sol. for inj. Mefloquine Tabl. 0.25 Pyrimethamine (Chloridine) Tabl. 0.01 Proquanyl h/chl. (Bigumal) Tabl. 0.1 Quinocide Tabl. 0.01

Glossary Gamontotropic medicines (gamontocides, sporocides) are medicines that act on the sexual cycle of plasmodia development in the human body (from a mosquito gets in the human body and the sexual cycle completion). Schizontocides are medicines that act on non-sexual forms of plasmodia, which develop in the human body. They are divided into hemato- and histoschizontocides, i.e. medicines that act on erythrocytic and tissue non-sexual forms of plasmodia, respectively.

164 ANTISYPHILITIC MEDICINES Antisyphilitic medicines act to the pale spirochete and are used for syphilis treatment.

Classification of medicines

Antibiotics Bismuth- Penicillins Cephalosporins Macrolides and Tetracyclines containing azalides* medicines Benzylpenicillin Cephaloridine Erythromycine Tetracycline Biyoquinol sodium and Azythromycine potassium salts

The mechanism of action Penicillins, cephalosporins inhibit the synthesis of the components of the spirochete cell wall (see ―Antibiotics‖). Macrolides, azalides, tetracyclines disturb the protein synthesis in the microbial cell (see ―Antibiotics‖). Bismuth-containing medicines block sulphohydryl groups of thiolic enzymes of the spirochetes and it causes inhibition of their tissue breathing resulting in death.

Pharmacodynamics (effects) → Indications Antibacterial (antispirochetal) effect Syphilis (all forms and stages) Side effects → Contraindications Bismuth-containing medicines: salivation, Dysfunctions of the liver, kidneys, ―bismuth border‖ on the gums, stomatitis, blood formation organs; pregnancy, colitis, nephrotoxicity, leukopenia, pain in the lactation site of injection

The pharmacological “face” of antisyphilitic medicines Medicines Type of Peculia- Toxi- Route of Other action rities of city administ- peculiarities Bc Bs action ration Benzylpenicillin + All stages + p/e AB of the medium of syphilis spectrum Cephaloridine + + p/e AB of the broad spectrum Azythromycine + + I, II stages + p/o AB of the broad of syphilis spectrum Tetracycline + +++ p/o AB of the broad spectrum Biyoquinol All stages ++ p/e Anti-inflammatory of syphilis effect, used in non- syphilitic diseases of the CNS

p/e- parenteral, p/o – peroral, AB – antibiotic.

165 The list of medicines INN, (Trade name) Medicinal form, dosage Azythromycine (Sumamed, Azythrocine) Tabl. 0,5 Benzylpenicillin sodium and potassium salts (Penicillin) Pwd. for inj. 1000000 U Biyoquinol Susp. 8% Cephaloridine Pwd. for inj. 0.25 Erythromycine Tabl. 0.2 Tetracycline Tabl. 0.1

Glossary Syphilis is an infectious disease caused by the pale spirochete. Stomatitis is inflammation of the mucous membrane of the oral cavity.

ANTIHELMINTHIC MEDICINES Antihelminthic (helminthicide) medicines are used to treat and prevent helminthiases (helminthic invasions). The majority of helminthiasis pathogens belong to nemathelminths (round worms, nematodes), flatworms (cestodes), flukes (trematodes). Helminthiases are respectively divided into nematodoses, cestodoses and trematodoses. Helminths parasitize in GIT (intestinal helminths), other organs: liver, gall bladder, blood and lymphatic vessels, subcutaneous fat (extraintestinal parasites). Ascarids, seatworms, hookworms, whipworms are nematodes that most frequently parasitize human intestines and cause ascariasis, enterobiasis, ancylostomiasis and trichocephaliasis respectively.

Classification of medicines Medicines used in Medicines used in Medicines used in intestinal nematodoses intestinal cestodoses and extraintestinal (*-broad spectrum ones) trematodoses* helminthiases Mebendazole* Aminoacrichine Prasiquantel Albendazole* Prasiquantel Mebendazole Mebendazole Albendazole tetrachloride* Prasiquantel* Tansy flowers

Mechanism of action Pyrantel, levamisole, aminoacrichine disturb the neuromuscular system functions in helminths. Albendazole and mebendazole disturb metabolic processes in helminths. Prasiquantel increases calcium ion permeability of cell membranes of helminths promoting the increase of their muscular tone turning into spastic paralysis. Ethylene tetrachloride has paralizing effect on helminths. Antihelminthic effect of Tansy flowers is caused by volatile oils present there.

Pharmacodynamics (effects) → Indications Antihelminthic effect Helminthiases (according to spectrum of action)

166 Side effects → Contraindications Dyspepsia Ulceration of GIT, liver diseases

Effective and safe use of antihelminthic medicines requires strict dosing regimen, special diet, simultaneous administration of laxatives, proper treatment scheme. As a rule, dosing and administration methods of any given antihelminthic medicine differ depending on the kind of helminthiasis. Mebendazole, Pyrantel, Prasiquantel do not require any preparation and special diet, administration of laxatives is also unnecessary. However, use of Ethylene tetrachloride and Tansy flowers requires special diet and administration of laxatives. As a rule, helminths do not develop resistance to medicines, and even in cases of recurrent invasions administration of the same medicine leads to full recovery. In the majority of cases in treatment of intestinal helminthiases it is recommended to use medicines on empty stomach to ensure maximal contact of the medicine with the parasite.

Pharmacological “face” of antihelminthic medicines Medicines Indications Ascaria- Entero- Cesto- Trichocepha- Ancylo- sis biasis doses liasis stomiasis Albendazole + + + + + Aminoacrichine + Levamisole* + Mebendazole + + + + + Pyrantel + + + Prasiquantel + * - it has immunostimulating effect.

The list of medicines INN, (Trade name) Medicinal form, dosage Albendazole Tabl. 0.2 Aminoacrichine Tabl. 0.3 Ethylene tetrachloride Levamisole (Decaris) Tabl. 0.05 Mebendazole (Vermox) Tabl. 0.1 Prasiquantel (Drontsit) Tabl. 0.6 Pyrantel (Combantrin) Tabl. 0.25, susp. 5% Tansy flowers Pack 75.0

ANTIFUNGAL MEDICINES Antifungal medicines are medicines used to treat fungous diseases (mycoses) and which in therapeutical dose, depending on pathogen kind, have fungicidal and/or fungistatic effect.

167 Classification of medicines Antifungal antibiotics Polyene structure ones and others* Amphoterycine B Nystatin Natamycine Griseofulvin* Antifungal medicines of synthetic origin Azoles ( N-methylnaphtha- Undecylenic acid Combined and triazole* lene derivatives, derivatives medicines derivatives) pyrimidines* Terbinafine Zincundan Clion D Ketoconazole Flucytosine* Pimafucort Miconazole Fluconazole* Itraconazole*

Mechanism of action The majority of antifungal medicines inhibit the main enzymes of ergosterol synthesis. Ergosterol is the main component of fungous cell wall, whereas in human cells cholesterol is the main steroid.

Pharmacodynamics (effects) → Indications Antifungal effect. Systemic and local Type of action: fungicidal and/or fungistatic mycoses Side effects → Contraindications Dyspepsia, teratogenicity (associated with resorptive GIT diseases, effect) pregnancy Amphoterycine B, itraconazole, fluconazole, ketoconazole have broad spectrum of antifungal activity.

Pharmacological “face” of antifungal medicines Medicines Effects Mycoses Absorption fc fs antimicrobial local systemic in GIT Amphoterycine + + + + Nystatin + + + ± Natamycine + + Griseofulvin + + Clotrimazole + + + + Ketoconazole + + + + + + Miconazole + + + + Fluconazole + + + + + + Itraconazole + + + + + + Terbinafine + + + Flucytosine + + + Zincundan + + + Clion D + + + + fc – fungicidal effect, fs – fungistatic effect.

168 The list of medicines INN, (Trade name) Medicinal form, dosage Amphoterycine B (Amphocyl) Tabl. 0.01 Clion D Vaginal tabl. Clotrimazole (Antifungol) Cream 1%, sol. 1% Fluconazole (Diflucan) Caps. 0.1 Flucytosine (Ancotil) Tabl. 0.5 Griseofulvin Tabl. 0.5 Itraconazole (Orungal) Caps. 0.1 Miconazole (Dactarin) Cream 2% Natamycine (Pimafucine) Cream 2% Nystatin (Mycostatin) Tabl. 500000 IU; ointment 100000 U/g Pimafucort Ointment 15.0 Terbinafine (Lamisil) Cream 1% Zincundan Ointment

Glossary Local mycoses are fungous diseases developing in the site of pathogen invasion, e.g. skin (dermatomycosis), nail (onychomycosis), hairy area of the head (trichomycosis), mucous membranes mycoses. Systemic mycoses are fungous diseases, in which the pathogen while circulating in blood affects different organs simultaneously (e.g. generalized candidiasis, histoplasmosis, blastomycosis etc.). Fungicidal effect is the ability of the medicine to cause death of a fungous cell. Fungistatic effect is the ability of the medicine to inhibit growth and reproduction of a fungous cell.

ANTIVIRAL MEDICINES Antiviral medicines are medicines used to prevent and treat viral diseases.

Classification of medicines

Anomalous Adamantane and other Pyrophosphate analogues nucleosides groups* derivatives Acyclovir Remantadine Sodium foscarnet Ribavirine Amantadine Gancyclovir Oxolin* Famcyclovir Interferons and Interferon synthesis HIV- proteinase and immunoglobulins* inducers reverse transcriptase (interferonogens) inhibitors* Interferon-(α-1, α-2B, Cycloferon Saquinavir β-1B) Amixin Nelfinavir Normal human Inosine pranobex Didanosine* immunoglobulin* Zidovudine*

169 Mechanism of action The main mechanism of the drug antiviral action is to inhibit an early stage of specific viral replication after their penetration into a human cell. Adamantane derivatives inhibit viral RNA release from protein, altering RNA penetration into cell nucleus. Anomalous nucleosides inhibit viral RNA and DNA synthesis. Pyrophosphate analogues inhibit viral DNA-polymerase. Interferons block viral- specific protein synthesis. Interferon synthesis inducers stimulate synthesis of endogenous interferon in human body. Interferon synthesis in human cells is human organism’s natural mechanism of protection against viruses. HIV-proteinase inhibitors inhibit viral proteinase through binding to specific receptors. Reverse transcriptase inhibitors disturb the process of replication and viral DNA formation through reverse transcriptase inhibition.

Pharmacodynamics (effects) → Indications Antiviral effect (all drugs). ARVI, herpes, influenza A, B; Immune-stimulating effect (interferons, encephalomyelitis, cytomegaloviral immunoglobulins, interferon synthesis infections, viral pneumonias, chickenpox, inducers) conjunctivitis, viral hepatitis (A, B, C), chlamydiasis Antiretroviral effect (antiviral effect HIV-infection against HIV-infection) Side effects → Contraindications Nephro- and hepatotoxicity, Renal and hepatic failure, pregnancy and teratogenicity, CNS disorders (tremor, lactation, epilepsy hallucinations, convulsions)

Pharmacological “face” of antiviral medicines

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170 Cycloferon + A, B, + A, B, + + + + P C, Δ Amixin + A, B, + A, B, C + P Inosine + + B, C + Saquinavir + Nelfinavir + Didanosine + Zidovudine + P – para-influenza, Δ – delta.

The list of medicines INN, (Trade name) Medicinal form, dosage Amantadine (Midantan) Tabl. 0.1 Amixin Tabl. 0.125 Acyclovir (Aclovir, Herpex, Zovirax) Tabl. 0.4, pwd. for inj. 0.25, ointment 5% Cycloferon (Neovir) Sol. for inj. 0.125 g/ml Didanosine (Videx) Tabl. 0.025 Famcyclovir (Famvir) Tabl. 0.25 Gancyclovir Caps. 0.25 Inosine pranobex (Groprinosine) Tabl. 0.5 Interferon β-1B (Betaferon) Lyoph. pwd. for inj. 9600000 U Interferon α-2B (Viferon) Supp. 150000 IU Interferon-α-1 Sol. for inj. 6000000 IU Normal human immunoglobulin Sol. 1.5 ml Nelfinavir (Virasept) Tabl. 0.25 Oxolin Ointment 3% Remantadine (Flumadine) Tabl. 0.05, syrup 10 mg/ml Ribavirine Tabl. 0.2 Saquinavir (Invirase) Caps. 0.2 Sodium foscarnet (Triapten) Cream 2% Zidovudine (Azatidine, Zidosan, Tabl., caps. 0.1, 0.25 Retrovir) Glossary Chickenpox is an infectious disease characterized by fever and vesicular rash. HIV-infection is a disease developed as a result of human immunodeficiency virus contamination and causing a state called ―acquired immunodeficiency syndrome, AIDS‖. Herpes is a viral disease caused by herpes viruses and characterized by vesicular rash appearing on skin and/or mucous membranes (herpes simplex) and along the nerve (herpes zoster). Influenza is a severe viral . Interferons are endogenous species-specific low-molecular proteins produced in cells as a response to viral, antigenic affection on the organism and protecting organism from being contaminated. Teratogenic effect is a negative effect of a medicine on a fetus resulting in possible severe abnormalities development. Encephalomyelitis is a brain or cerebrospinal inflammation.

171 XV. ANTITUMOUR MEDICINES

Antitumour (antiblastic, antineoplasm, etc.) medicines are medicines that suppress the development of atypical cells of true tumours (cancer, sarcoma, etc.) and hemoblastoses (leukemia, etc.). Antitumour medicines are widely used in the oncological practice supplementing surgery and radiation therapy, and they are the only method of treatment in some tumourous processes (leukemia, lymphogranulomatosis). Classification of medicines 1. Alkylating compounds Derivatives of Derivatives of Derivatives of Derivatives of chlorethylamine ethylenimine sulphonic acid nitrosourea, hydroxyurea Chlorethylaminouracil Thiophosphamide Busulphan Nimustine Cyclophosphamide Phosphemide Hydroxycarba- mide Metal-organic compounds Other alkylating compounds Cisplatin Dacarbazine 2. Antagonists of the Antagonists of the Antagonists of folic acid purine bases pyrimidine Methotrexate Mercaptopurine Fluorouracil 3. Cytostatics of the plant origin Alkaloids of Vinca rosea Alkaloids of Podophyllum Alkaloids of (vinca alkaloids) (podophyllotoxins) Colchicum speciosum Vincristine Podophylline Colchamine of Taxus tree (taxozides) 4. Hormonal and antihormonal medicines Gestagens Estrogens Antiestrogens Androgens Ethynylestradiol Tamoxyphen Testosterone Ciproterone propionate acetate Analogues of gonadoliberin Inhibitors of adrenal cortex hormones biosynthesis Gozerelin Aminoglutetimide 5. Antitumour antibiotics 6. Inhibitors of topoisomerase I, aromatase* Actinomycines Anthra- Phleomycines Topothecan Anastrozol * cyclines Dactinomycine Doxorubicine Bleomycine 7. Cytokins 8. Enzymes Aldesleukin L-asparaginase 9. Recombinant monoclonal antibodies Trastusumab

172 The mechanism of action Alkylating medicines are nitrogenous compounds, whose mechanism of action is connected with transferring the alkyl radical to the receptor of other molecule. Quaternary ammonium derivatives with a high reactivity, which are forming, react (alkylate) with such physiologically important groups of the cell molecules as amino-, sulphohydryl-, hydroxyl-, phosphatic ones. As a result, the latter ones lose their possibility to participate in metabolic processes. Besides, alkylating medicines suppress the biosynthesis of nucleic acids and the ability of tumour cells to divide, damage mitochondrial membranes, alter the processes of oxidation and phosphorylation, break irreversibly the structure and the functions of tumour cells in any functional stage. medicines are similar to metabolites by their chemical structure: they are modified molecules of aminoacids, purines and pyrimidines, i.e. precursors of nucleic acids, folic acid, vitamins and hormones. The mechanism of action of antimetabolites is an ability to form competitively the bonds with receptors instead of the normal metabolites. Antimetabolites substitute them in biochemical reactions but they cannot perform their functions. As a result, the course of the vital biochemical processes in the cell, in particular the DNA and RNA synthesis inside a tumour cell, becomes slow. Thus, antimetabolites become pseudometabolites for the cells, metabolically inactive or even toxic substances. Sometimes this process is called ―the lethal synthesis‖. The action of cytostatics of the plant origin is explained by their ability to block the cell mitosis in the phase of metaphase and inhibit the DNA synthesis. Medicines bind to tubuline, the protein of microtubules, inhibit the formation of the mitotic spindle and as a result the cell division is blocked. Camptothecines – irinothecan and topothecan – have been obtained from the plant Camptothecana acuminata for the first time. According to their mechanism of action they are inhibitors of topoisomerase I, which takes part in the DNA synthesis and provides its spacious configuration, reparation if damaged, replication and transcription. As a result, the growth of tumour cells is inhibited. Hormonal medicines form complexes with hormonal receptors, penetrate into the cell nucleus, bind to chromatin and break the synthesis of nucleic acids in target cells (sensitive to a certain hormone). So, gestagens and androgens suppress the production of the pituitary gonadotropins and it leads to the inhibition of the estrogen synthesis. The analogues of gonadoliberin turn off the hormone-synthesizing function of testes and ovaries (i.e. cause the pharmacological castration). Antiestrogens bind specifically to estrogen receptors of the mammary gland tumours. As a result, the stimulating effect of the endogenous estrogens disappears. Antiandrogens block competitively androgen receptors in target tissues and it leads to the suppression of the physiologic activity of endogenous androgens. Inhibitors of aromatase block the enzyme aromatase in the peripheral tissues and it leads to the decrease of the estradiol amount. Aminoglutetimide inhibits the biosynthesis of corticosteroids, as well as estrogens and androgens. Antitumour antibiotics form stable complexes with the cell DNA that leads to disorder of the DNA-dependent synthesis of RNA and replication of the tumour cell.

173 The mechanism of their cytotoxic action is related with the introduction (intercalation) between two DNA filaments, inhibition of topoisomerase II, and formation of free radicals. Hence, another name of these medicines is intercalants. Cytokins stimulate cytotoxic T-killers and natural killers and it is accompanied by the release of γ-interferon, interleukin-2 (mediators of immune reactions). The enzymatic medicine L-asparaginase decreases the L-asparagine synthesis, which is important for the growth of tumour cells. Trastusumab, which contains recombinant humanised monoclonal antibodies to the receptor of the epidermal growth factor, inhibits selectively the proliferation of malignant cells.

Pharmacodynamics (effects) → Indications Antitumour medicines have cytostatic, cytotoxic and Tumours of different immune-suppressive effects (all, except hormonal and location antihormonal ones). Hormonal and antihormonal medicines retard the division of hormone-dependent tumour cells and promote their differentiation, have androgenic (androgens), antiandrogenic (antiandrogens, estrogens), estrogenic (estrogens), antiestrogenic (gestagens, antiestrogens, inhibitors of the adrenal glands hormones biosynthesis) effects; inhibit hormone synthesizing function of testes and ovaries - cause the pharmacological castration (analogues of gonadoliberin); cause the pharmacological andrenalectomy (aminoglutetimide) Side effects → Contraindications Inhibition of the blood formation, Inhibition of the hemopoiesis, immune immune suppression, dyspepsia; deficiency, peptic ulcer (with caution); mutagenicity, teratogenicity pregnancy, lactation

The pharmacological “face” of antitumour medicines (A) Indications Medicines Leukosis (leukemia) 1, 2, 3, 4, 5, 10, 11, 13, 16, 26, 27, 30 Cancer of the uterus 2, 7, 8, 9, 10, 11, 12, 13, 17, 19, 20, 24, 25, 26 Cancer of the stomach 8, 12, 24, 25, 26 Mammary gland cancer 1, 2, 8, 10, 12, 13, 16, 17, 19, 20, 22, 23, 25, 28, 30, 31 Lung cancer 2, 6, 7, 8, 10, 13, 24, 25, 26 Lymphogranulomatosis 1, 2, 7, 8, 9, 13, 24, 25, 26, 30 Tumours of the brain 6, 7, 27, 26 Melanoma 6, 7, 9, 13, 24 Cancer of the esophagus 6, 14, 16 Cancer of the penis 26 Cancer of the thyroid gland 25, 26 Cancer of the ovaries 2, 7, 8, 10, 12, 17, 19, 20, 21, 22, 23, 25,

174 26 Cancer of the prostate 2, 8, 10, 12, 17 , 19, 20, 24, 25, 26 Sarcoma 2, 8, 9, 10, 13, 24, 25, 26 Cancer of the urinary bladder 2, 8, 12, 13, 16, 25 Skin cancer 15, 26 Cancer of the pancreas 12, 25 Cancer of the liver 25 Cancer of the testicle 2, 8, 24, 26 Cancer of the kidney 2, 10, 13, 29, 24, 26 Cancer of the head, neck 7, 8, 10, 12, 13, 16, 25, 26, 27 Cancer of the adrenal cortex 8 Ewing’s tumour 2, 10, 9 Myeloma 2, 9, 10, 25, 29 Lymphosarcoma, T-cells lymphoma, 30, 7* erythremia* Numbers 1-31 are the numbers of medicines in classification.

The pharmacological “face” of antitumour medicines (B) Medicines Peculiarities Chlorethylaminouracil Hypocholesterolemic effect Cyclophosphamide It is a ―premedicine‖, also used in autoimmune diseases Bisulphan Resistance to the medicine can appear Nimustine They penetrate through the blood-brain barrier Hydroxycarbamide Cisplatin It doesn’t penetrate through the BBB Methotrexate Anti-inflammatory effect, it is used in dermatosis, rheumatoid arthritis Mercaptopurine It is used in autoimmune diseases, resistance develops quickly Fluorouracil It is quickly inactivated and it requires frequent intakes Podophylline Laxative, choleretic effects Paclitaxel Treatment of multiple idiopathic hemorrhagic sarcoma in AIDS patients Megestrol It is used in anorexia and cachexia Ethynylestradiol It is used in hormonal disorders of non-tumour origin Testosterone Male hypersexuality, female hyperadrogenisation Gozerelin Depo-medicine (introduced once a month) Aminoglutetimide Anticonvulsant effect, decreases the synthesis of GC, MC. It is used in hypocorticism, hypertension Doxorubicine Cardiotoxicity Bleomycine It increases the sensitivity of a tumour to radiation therapy Aldesleukin It has the immune-modulating effect

175 The list of medicines INN, (Trade name) Medicinal form, dosage L-asparaginase Pwd. for inj. 10000 U Aldesleukin (Proleukin) Pwd. for inj. 0.0012 Aminoglutetimide (Mamomit) Tabl. 0.25 Anastrozol (Arimidex) Tabl. 0.001 Bleomycine (Bleocine) Pwd. for inj. 0.015 Busulphan (Myelosan) Tabl. 0.002 Chlorethylaminouracil (Dopan) Tabl. 0.002 Cisplatin (Platidiam) Sol. for inj. 0.1% Colchamine Tabl. 0.002, ointment 0.5% Cyclophosphamide Tabl. 0.05, pwd. for inj. 0.5 Cyproterone acetate (Ciprostat) Tabl. 0.01, sol. for inj. 10% Dacarbazine (Biocarbazine) Pwd. for inj. 0.1 Dactinomycine Sol. for inj. 0.05% Doxorubicine (Adriablastin) Pwd. for inj. 0,01 Ethynylestradiol (Microfollin) Tabl. 0.01 Fluorouracil (Flurox) Sol. for inj. 5% Gozerelin (Zoladex) Tabl. 0.0036 Hydroxycarbamide Caps. 0.5 Megestrol Tabl. 0.04 Mercaptopurine Tabl. 0.05 Methotrexate (Trexan) Tabl. 0.005, sol. for inj. 1% Nimustine Pwd. for inj. 0.05 Paclitaxel (Taxol) Concentrate for inj. 6% Phosphemide Pwd. for inj. 0.02 Podophylline Pwd. 100.0 Tamoxyphen Tabl. 0.02 Testosterone propionate (Andriol) Sol. for inj. 5% Thiophosphamide (Thiotepa) Pwd. for inj. 0.01 Topotecan (Gicamptine) Sol. for inj. 0.004 Trastusumab Pwd. for inj. 0.44 Vincristine (Onkovin) Sol. for inj. 0.1%

Glossary Adrenalectomy is the removal of the adrenal glands. Immune-suppressive effect is inhibition of the antibody production and the immune response. Cytostatic effect is the action that preceedes the cytotoxic effect and is revealed as retardation of the tumour cell growth. Cytotoxic effect is destruction of the nucleus and death of growing tumour cells in the state of division.

XVI. IMMUNOSTIMULANTS

Immunostimulants are used in the states of immune deficiency, chronic infections, in some cancer diseases, etc.

176 Pharmacological description

Medicines Group Origin/ Pharmacological «face» composition Thymalin Polypeptide They normalize T-lymphocytes and Tactivin fractions their ratio with B- lymphocytes, from the - cellular immunity reactions; increase tle’s thymus the activity of natural killers, intensify phagocytosis and production of lymphokins. They are used in burns, trophic ulcers, inhibition of Endoge- hemopoiesis, immunity, in radiation nous and Myelopid polypep- Cell culture It stimulates proliferation and the tides of bone mar- functional activity of T- and B-killers. row of calves, It is used in secondary immune pigs deficiency states (the humoral immunity), for prevention of complications after operations and traumas Immunofan Synthetic It stimulates interleukin-2 formation, hexopeptide decreases the production of the tumour necrosis factor, regulates the production of immunity mediators and immunoglobulins. It is used in immune deficiency states Levamisole Synthetic Imidazole It regulates differentiation of T- medicines derivative lymphocytes, promotes the synthesis (see of immunoglobulins ―Antihelmint hic medicines‖) Polyoxydo- Synthetic Immune-stimulating, detoxication nium polymer effects

Broncho- Microbial Bacteria It stimulates the humoral and cellular munal medicines lyophylic immunity, increases the amount and and their lysate activity of lymphocytes and analogues immunoglobulins A, G, M, cytokins in the mucous membrane of the respiratory tract. It is used in infections of respiratory tract, resistant to the antibiotic therapy

177 Prodigiosan Complex It increases non-specific and specific from resistance of an organism (activates B- microorganis lymphocytes, interferons, lysocim, ms B. complement). It is used in chronic in- prodigiosum flammations, poor healing of wounds, radiation therapy Interferon α, Interfe- Natural and It has antiviral, anti-inflammatory, β*, α-2a, β- rons recombinant* immune-stimulating effects. It is used 1b* in herpes, hepatitis B, C, HIV- infection, influenza and ARVI, etc. Amixin Interfe- Low- A broad spectrum of the antiviral ron molecular action against DNA- and RNA- synthesis synthetic containing viruses (see ―Antiviral inducers agent medicines‖) Poludan The It affects viruses of a simple herpes biosynthetic (herpes conjunctivitis, keratitis, polyribonucle iridocyclitis, etc.) ic complex Cycloferon Low- Antiviral (see ―Antiviral medicines‖), molecular anti-inflammatory, immune-stimula- compound ting, antichlamydial, radioprotective effects. It is used in tick-borne encephalitis, herpes, cytomegalovirus and HIV-infections; in collagenoses

Roncoleukin Inter- Recombinant Immune-stimulating, antitumour leukins analogue of effects. It increases proliferation of T- interleukin-2 lymphocytes and interleukin-2- dependent acids, cytotoxicity of lymphocytes and killers of tumour cells, production of γ-interferon, interleukin-1, the tumour necrosis factor. It is used in cancer of kidneys Betaleukin Recombinant Increases leukopoiesis and immunity. human Used in chemo- and radiation therapy interleu- of tumours, immune deficiencies kin-1 Molgra- Colony- Recombinant See ―Leukopoiesis stimulants‖ mostim, stimula- human Filgrastim, ting colony- Lenograstim factors stimulating factors

178 Normal hu- Immunoglobulin G It is used in immune man immuno- deficiency states, globulin thrombocytopenic purpura, Human etc. Pentaglobin immuno- Immunoglobulin G en- It is used in severe bacterial globulins riched by im- infections (sepsis), immune munoglobulins М, А deficiencies Cytotect Specific hyperimmune It is used in cytomegaloviral immunoglobulins G infections Hepatect against the certain It is used in hepatitis В pathogens

The list of medicines INN, (Trade name) Medicinal form, dosage Amixin Tabl. 0.125 Betaleukin Lyoph. pwd. for inj. 0.001 Bronchomunal Caps. 0.0035 Cycloferon Sol. for inj. 12.5%, tabl. 0.15 Cytotect Sol. for inj. 10% Hepatect Sol. for inj. 50 U/ml Immunofan Sol. for inj. 0.005% Interferon α Lyoph. pwd. for inj. 1 mln U Interferon β Lyoph. pwd. for inj. 1 mln U Interferon-α-2a (Roferon A) Lyoph. pwd. for inj. 3 mln U Interferon-β-1b (Betaferon) Lyoph. pwd. for inj. 9600000 U Myelopid Lyoph. pwd. for inj. 0.003 Normal human immunoglobulin Sol. for inj. 5% Pentaglobin Sol. for inj. 5% Poludan Lyoph. pwd. 100 U Polyoxydonium Lyoph. pwd. for inj. 0.003 Prodigiosan Sol. for inj. 0.005% Roncoleukin Lyoph. pwd. for inj. 0.001 Tactivin Sol. for inj. 0.01% Thymalin Lyoph. pwd. for inj. 0.01

Glossary Interleukins (IL) is a group of lymphokins acting as growth and differentiation factors of lymphocytes (approximately 20 of them have been described) and they perform complex of intercellular interactions involved into the immune response. Immunoglobulins (Ig) is the class of proteins structurally related that participate in immune reactions (being antibodies by their functions). The tumour necrosis factor (TNF) is a cytotoxin produced by macrophages that causes necrosis of some tumours and activates neutrophils stimulating the synthesis of cytokins.

179 XVII. MEDICINES FOR DYSBIOSIS TREATMENT Up to 90% of microbes of the large intestine are bifidobacteria, which have a positive effect on the activity of GIT organs, cardiovascular system, blood formation, immunity; improve digestion of proteins, carbohydrates, fats; provide absorption of vitamins E, K, B, PP, D and the synthesis of aminoacids, antibodies, immunoglobulins, interferon and cytokins. The normal microflora of the large intestine supports pH=5.3-5.8 and because of this the pathogenic putrefactive and gas-forming microflora perishes. Decompensated dysbiosis (dysbacteriosis) (indication for these medicines), dysfunction of the normal microflora composition (in particular, the intestinal) is the result of a severe intestinal infection or use of the incorrect scheme of chemotherapeutics administration.

Classification of medicines Medicines normalizing the flora: stimulating the normal inhibiting the conditional probiotics - flora growth: pathogenic microflora: monocomponent, prebiotics and symbi- bacteriophages and polycomponent *, otics* others* combined ** Lactobacterin Potassium permanganate Staphylococcal and Bactisubtil Hilak-forte pseudomonal Linex* Lactulose bacteriophages Bificol* Bifiform* Fluconazole* Bifidumbacterin forte* Natamycine* Ketoconazole*

The mechanism of action Promote the formation of Decrease pH of the large Destroy the conditional- the acetic, lactic acids in intestine. Contain the pathogenic flora; the intestine inhibiting the components necessary for fungicidal and fungistatic putrefactive and gas- nutrition and reproduction effects against Candida forming flora of bifidobacteria and fungi lactobacteria

Pharmacodynamics Support the balance of the normal Stimulate the growth and Antibacterial, microflora; reduce meteorism, reproduction of the antifungal normalize digestion and normal microflora of the effects absorption in the intestine; intestine, strengthen the promote the organism’s resistance peristalsis of the GIT to infection

Side effects → Contraindications Seldom – dyspepsia (all); meteorism Infants before 6 months (Bificol); liver (Lactulose, Fluconazole); diseases, pregnancy, lactation hepatotoxicity (Fluconazole) (Ketoconazole); porphyria (Natamycine); intestinal obstruction

180 Side effects and contraindications have not been determined for Bactisubtil, Bifidumbacterin forte, Bificol, Bifiform, Potassium permanganate, Lactobacterin and Linex.

The pharmacological “face” of medicines for dysbiosis treatment Medicines Dysbiosis Other indications Com- Subcom- Decom- Acute Diarrhea Chronic pensa- pensated pensated intestinal in entero- ted infections children colitis All, except + + + +** Hilak- +* Fluconazole@, forte, Natamycine @, Lactobac Ketoconazole @ -terin * - except bacteriophages inhibiting conditional pathogenic flora; ** - only probiotics; @ - except dysbiosis it is used in mycoses.

The list of medicines INN, (Trade name) Medicinal form, dosage Bactisubtil Caps. 0.035 Bificol Packs Bifidumbacterin forte Packs Bifiform Caps. Fluconazole Tabl. 0.2 Hilak-forte Liquid 100ml Ketoconazole Tabl. 0.2 Lactobacterin Lactulose Pwd. 10.0 Linex Caps. Natamycine Tabl. 0.1, cream 30.0, supp. 2.5% Potassium permanganate Pwd. 3.0 Staphylococcal and pseudomonal bacteriophages

Glossary Probiotics are medicines, which contain living weak microorganisms. Prebiotics are substances of non-microbial origin, which promote the growth and development of the normal intestinal microflora. Symbiotics are combined medicines containing probiotics and prebiotics.

XVIII. ANTI-ALLERGIC MEDICINES Anti-allergic medicines are medicines for prevention and treatment of allergic diseases. Traditionally allergic reactions (hypersensitivity reactions) are divided into: immediate type reactions (they develop in some minutes after the repeated contact with an allergen): anaphylactic shock, angioneurotic edema, serum disease, urticaria, pruritus, pollen fever; retarded (slow) type reactions (they are revealed in 2-3 days

181 and more): reaction of graft rejection, contact dermatitis, autoimmune diseases. Histamine takes the specific place in the pathogenesis of allergic reactions. It is contained mainly in the Erlich mastocytes (located along the tiny vessels, in the bronchial tissue, in the intestine), as well as in basophiles, leukocytes and it is inactivated by histaminase. Histamine is the natural ligand of 4 subtypes of histamine receptors: H1-, H2-, H3- and H4-receptors. Allergic reactions are connected with stimulation of H1-receptors located in the smooth muscles of the bronchi, intestine, biliary and urinary tracts, heart and blood vessels. In ordinary conditions histamine is found in the inactive (bound) state, but in allergic reactions the quantity of free histamine sharply rises, and it leads to activation of H1-histamine receptors, which is revealed in the increase of the smooth muscles tone of the bronchi, intestine and uterus; decrease of the blood pressure (partially), increase of the capillaries permeability with the edema development, hyperemia and pruritus development. Serotonin together with histamine takes part in the development of all allergic reactions. The peripheral action of serotonin is connected with the stimulation of serotonin receptors, that leads to contraction of the smooth muscles of the uterus, intestine and bronchi, and contraction of blood verssels; increase of the thrombocytes aggregation.

Classification of medicines Blockers of H1-histamine receptors Blockers of serotonin* receptors, combined** agents Ciproheptadine* Terfenadine Loratadine Clarinase** Diphenhydramine Membrane stabilizers Glucocorticosteroids Selective antagonists of leukotriene receptors Cromoglycic acid Prednisolone Zafirlucast

The mechanism of action Medicines of this group cause their anti-allergic effect affecting different links of the allergy pathogenesis. Antihistaminic medicines (blockers of H1-histamine receptors) block H1- receptors due to competitive antagonism with histamine and eliminate the increased sensitivity of the cell membranes (especially smooth muscles) to the free histamine. Ciproheptadine blocks histamine and serotonin receptors and decreases production of cytokines. Membrane stabilizers block the calcium ions flow into mastocytes inhibiting their degranulation and, thus, preventing the release of the mediators of allergy and inflammation: histamine, bradykinin, serotonin and other biologically active substances. The mechanism of action of glucocorticosteroids in the allergic inflammation is decrease of histamine and serotonin synthesis; potentiation of the catecholamines effects; inhibition of cholinergic effect; inhibition of plasma and granulocytes leaving from capillaries; decrease of the amount of leukocytes, eosinophils, neutrophils, lymphocytes in the site of inflammation; inhibition of the phospholipase A2 activity (as a result the release of the and the

182 formation of its metabolites are prevented, in particular leukotrienes and a slow reacting substance of anaphylaxis). Selective antagonists of leukotriene receptors are competitive antagonists of LTC4-, LTD4- and LTE4- receptors (components of a slow reacting substance of anaphylaxis). Clarinase is a combined medicine containing pseudoephedrine and loratadine. Loratadine blocks H1-histamine receptors, pseudoephedrine reduces edema of the mucuos membranes.

Pharmacodynamics (effects) → Indications Anti-allergic effect Allergic reactions (anaphylactic shock, bronchial asthma, dermatitis, angioneurotic edema, etc.) Side effects → Contraindications Inhibition of the CNS (decrease of The activity that requires attention, attention, sedative effect), cardiotoxic craniocerebral trauma, hypertension, liver effect, hypotension diseases, pregnancy, lactation

The pharmacological “face” of anti-allergic medicines Medicines Recep- Effects Duration Other effects tors Spas- Seda- Anti- of action blockers mo- tive inflam- lytic matory Promethazine (Ι) H1+H2 + + + 8-12 Local anesthetic, potentiating, hypnotic Clemastine (Ι) H1+H2 + + + 6-10 Ciproheptadine H1+H2 + + + 8-12 Appetite increase Terfenadine (ΙΙ) H1 + 12-24 Loratadine (ΙΙ) H1 + + 12-24 Antipruritic Cromoglycic acid + + 2-4 Prednisolone + + 8-12 Immunity decrease Triamcinolone + + 8-12 Immunity acetonide decrease, antipruritic

Zafirlucast + 12 Incompatible with food. A strict doctor’s control is necessary

Diphenhydramine H1+H2 + + + 4-6 Potentiating, (Ι) hypnotic Ι, ΙΙ –generations of histamine-blockers

183 The list of medicines INN, (Trade name) Medicinal form, dosage Ciproheptadine (Peritol) Tabl. 0.004 Clarinase Tabl. Clemastine (Tavegil) Tabl. 0.001 Cromoglycic acid (Intal) Aerosol 2%, sol. 2% Diphenhydramine (Dimedrol) Tabl. 0.05, sol. for inj. 1% Loratadine (Claritine) Tabl. 0.01 Prednisolone Tabl. 0.001, ointment Promethazine (Diprasine, Pipolfen) Tabl. 0.005, sol. for inj. 2.5% Terfenadine Tabl. 0.06 Triamcinolone acetonide (Fluorocort) Ointment 0.025% Zafirlucast (Acolat) Tabl. 0.02

Glossary Allergy (in Greek allos is ―other‖ and ergon is ―action‖) is a state of the organism’s increased sensitivity to the repeated affection of allergens. Leukotrienes are the class of biologically active substances synthesized in the arachidonic acid cascade, which take part in the development of allergic and inflammatory reactions. A slow reacting substance of anaphylaxis is substances produced by mastocytes during an allergic reaction (the mixture of leukotrienes C4, D4, E4) causing a slow contraction of smooth muscles, which is more prolonged than that caused by histamine.

XIX. MEDICINES THAT USED IN POISONINGS (ANTIDOTES) Antidotes are medicines that are able to make a poison (which is in blood or bound to biological substrates) harmless in case of intoxication and/or remove the toxic effects of a poison or accelerate its elimination. Medicines The Pharmacodynamics Indications mechanism of (poisonings) action Activated Absorption of a Decrease of the poison Food toxical infection, carbon, poison absorption in the GIT, poisoning by orally Polyphepan its elimination administered poisons Dipyroxim, Restoration of Normalization of the Poisoning by irreversible- Isonitrosine the cholinergic acting anticholinesterase cholinesterase neurotransmission medicines, FOC activity Unithiol Formation of Reduction of the Poisoning by heavy low toxic water thiolic enzymes metals, cardiac soluble activity, binding to glycosides, arsenic complexes with thiolic poisons thiolic poisons Calcium Formation of Elimination of a Poisoning by metals trisodium chelate poison in form of

184 pentetate, complexes with stable poorly Sodium 2-, 3-valency dissociated non-toxic Calcium metals complexes edetate, Sodium edetate Sodium nitrite, Conversion of Binding of cyanides Poisoning by cyanides Amylnitrite hemoglobin into methemoglobin, which reacts cyanides well with Methylene blue Depending on Conversion of Poisoning by cyanides, the dose it plays methemoglobin into nitrates, aniline and the role of hemoglobin in small carbon monoxide donor or doses, transfering of acceptor of hemoglobin into electrons methemoglobin in high doses Ethyl alcohol Retardation of Decrease of Poisoning by (ethanol) the methanol formation of highly metabolism toxic formaldehyde Atropine Blockade of M- Decrease of Poisoning by direct-acting sulphate cholinorecep- parasympathetic cholinomimetics tors effects Neostigmine Reversible Increase of Poisoning by atropine, methylsulphate inhibition of parasympathetic belladonna-containing acetylcholine- effects on the internal medicines, antidepola- esterase organs rizing myorelaxants Antagonism Removal of the Poisoning by narcotic with opiate narcotic analgesics analgesics (the group of receptors effects morphine) Bemegride Direct Stimulation of Poisoning by hypnotics stimulation of breathing, increase of (barbiturates), other CNS the respiratory the blood pressure depressants and vasomotor centres Protamine Antagonism Increase of blood Overdosage of heparin sulphate with heparin coagulation Flumazenyl Competitive Removal of the Overdosage of blockade of tranquilizers effects; benzodiazepine benzodiazepine anticonvulsant effect tranquilizers receptors FOC- phosphorus-containing organic compounds ().

185 Besides the medicines mentioned diuretics, plasma substituted medicines, methods of hyperbaric oxygenation and hemodyalysis are used in poisonings. To restore the life important functions, if it is necessary, analeptics, hypertensive, antiarrhythmic and other medicines, as well as apparatuses for artificial ventilation of lungs are used.

The list of medicines INN, (Trade name) Medicinal form, dosage Activated carbon (Carbolong) Tabl. 0.25 Amylnitrite Sol., amp. Atropine sulphate Sol. for inj. 0.1% Bemegride Sol. for inj. 0.5% Calcium trisodium pentetate (Pentacine) Sol. for inj. 5% Dipyroxim Sol. for inj. 15% Ethyl alcohol (Ethanol) Liquid, vial 50 ml (as antiseptic) Flumazenyl Sol. for inj. 0.01% Isonitrosine Sol. for inj. 40% Methylene blue Sol. for inj. 1% Nalorphine Sol. for inj. 0.5% Neostigmine methylsulphate (Proserin) Sol. for inj. 0.05% Polyphepan (Entegnine) Pwd., packs 10.0 Protamine sulphate Sol. for inj. 1% Sodium calcium edetate (Tetacine-calcium) Sol. for inj. 10% Sodium nitrite Sol. for inj. 1% Sodium edetate (Trilon B, EDTA) Sol. for inj. 5% Unithiol Sol. for inj. 5%

Glossary Phosphorus-containing organic compounds (insecticides: chlorophos, dichlophos and others) are substances of agricultural and household chemistry, however, they are similar to irreversible-acting anticholinesterase medicines by the mechanism of action and the symptoms of poisoning.

XX. MEDICINES OF DIFFERENT PHARMACOLOGICAL GROUPS

Since therapy of many diseases is complex, and many medicines have a wide spectrum of pharmacological action, there are pharmacological groups or separate medicines, which belong to several pharmacological groups simultaneously. Along with the main effects that are characteristic for the certain group, they have some additional pharmacological properties used for pharmacological correction of various diseases. Besides, modern classification of medicines often forms the so-called «combined groups» where there are medicines, representatives of different pharmacological groups. Therefore, it is necessary to systematize these medicines in one section (see tables).

186 Table 1 Group It is described in the corresponding groups or in table 2* Hypertensive Analeptics, psychomotor stimulants, adaptogens, medicines adrenomimetics (α1, α + β). Dophamine*, Angiotensinamide* Gastroprotectors Antiulcer medicines (bismuth-containing medicines, astringents, covering medicines, cytoprotectors – prostaglandins analogues) Inhibitors of Enzymatic and anti-enzymatic medicines (Aprotinine); proteases (anti- medicines increasing blood coagulation (Aminocapronic enzymatic) acid) Prokinetics *, Methoclopramide* Anti-aggregants Medicines decreasing blood coagulation (Aspirin, Dipyridamol, Ticlopidine). Аbcyximab* Cholelitholytic Hepatoprotectors (Ursodeoxycholic acid). medicines Chenodeoxycholic acid* Cholagogue Hepatoprotectors (Flamine). Allochol*, Himechromone* (choleretic) medicines Normothymics Anticonvulsants (Carbamazepine, valproates), calcium antagonists (Verapamil, Dilthiazem, etc. – see anti-anginal, hypotensive, anti-arrhythmic medicines). Salts of lithium* (carbonate, gluconate, chloride, etc.) Antidiarrheal Inhibitors of hypophysis hormones secretion (Synthetic medicines somatostatin*). Nifuroxaside*, Hilac forte *, Smekta*, * Enzymatic medicines Pancreatic enzymes; medicines decreasing blood coagulation (fibrinolytics). Hyaluronidase*, Trypsin*, Cytochrome C *, Penicillinase*, Deoxyribonuclease* Immunotropic: - glucocorticosteroids, antitumour medicines (alkylating - immunodepressants medicines, antibiotics, etc.), antibiotics. Thymoglobulin*, Аzathioprin*, Daclizumab*, Cyclosporin*

- immunostimulants - Antihelminthic (Levamisole), antiviral (interferons and their inducers), leukopoiesis stimulants, immunostimulants, hypotensive medicines (bendazole)

Table 2 The pharmacological “face” of medicines Dophamine Hypertensive (stimulant of dophamine receptors, α, β-АR). It acts dose-dependently: in small doses it dilates vessels of the kidneys and intestine; in average ones it has the cardiostimulating effect, increases the coronary blood flow; in high doses - ↑ TPVR, constricts renal vessels. It is used in hypotension, shock of different etiology

187 Аngiotensi- Hypertensive (amide of the natural angiotensin II). ↑ TPVR, namide secretion of adrenaline and aldosterone. It is used in shock and related vasomotor collapse Domperi- Prokinetics (D2-dophamine receptors blocker). It intensifies the GIT done peristalsis, has anti-emetic effect. It is used in dyspepsia with the gastro-enteral reflux, esophagitis; nausea and vomiting of various genesis Metho- Prokinetics (blocker of dophamine and serotonin receptors). It clopramide regulates the tone and peristalsis of the GIT. It has anti-emetic, antinausea effects. It is used in intestinal paresis, nausea and vomiting after operation, radiation and chemotherapy Аbcyximab Anti-aggregant (contains monoclonal antibodies). It inhibits non- competitively binding of fibrinogen to glycoproteins IIb/IIIа in the membrane of thrombocytes, disturbs their aggregation. It is used to prevent thromboses Chenode- Cholelitholytic. It decreases the synthesis, absorption of cholesterol oxycholic and formation of cholesterol stones in the gallbladder. It is used in acid cholelithiasis Allochol Cholagogue (choleretics). It contains bile, extracts of and belladonna, activated carbon. It intensifies formation and excretion of bile. It is used in hepatites, cholecystitis Himechro- Cholagogue (synthetic choleretics). It intensifies reflexively bile mone secretion, prevents formation of stones, has spasmolytic effect on the biliary tract. It is used in dyskinesia of the billiary tract, cholecystitis, hepatitis with cholestasis Lithium Normothymics. They correct the mood disorders, have antimaniac salts and antidepressant effects. They are used during phasic psychotic mood disorders Synthetic Antidiarrheal. It decreases secretion of somatotropin and insulin, somatosta- production of gastric juice, inhibits the GIT peristalsis. It is used in tin intractable diarrhea, acromegalia, tumours of the gastro-entero- pancreatic system Nifuroxa- Antidiarrheal (synthetic antibacterial). It is used in bacterial side diarrhea Hilac forte Antidiarrheal (embryoless water substrate of metabolism products of the normal intestinal microflora). It normalizes the microflora in dysbiosis, diarrhea Smekta Antidiarrheal (adsorbing agent). It stabilizes the mucous bicarbonate barrier of the mucous membrane of intestine and stomach, protects it from aggression of food, microbial toxins, hypersecretion; prevents the affection of digestive enzymes on it. It is used in diarrhea Loperamide Antidiarrheal (agonist of the peripheral opiate receptors). It is used in diarrhea Trypsin Enzymatic (proteolytic enzyme). It dilutes viscous secretions,

188 exudates, blood clots, splits, necrotized tissues due to the destruction of peptide bonds in protein molecules. It is used for expectoration, in burns, purulent wounds, commissure processes, iridocyclitis Deoxyri- Enzymatic (proteolytic enzyme). See ―Trypsin‖ + antiviral effect. It bonuclease is used in bedsores, keratitis, conjunctivitis Hyaluroni- Enzymatic medicine. It increases tissue permeability decreasing dase viscosity of hyaluronic acid; softens scars, removes contractures in joints, hematomas. It is used in hematomas, contractures in joints, rheumatoid arthritis Cytochrome Enzymatic. It improves tissue breathing, restores oxidative processes. C It is used in asphyxia of newborns, chronic pneumonia, HF, IHD, hypoxia Penicilli- Enzymatic. It inactivates penicillins destroying the β-lactam ring. It nase is used in acute allergy caused by penicillins Thymoglo- Immunodepressant (polyclonal antibodies, antithymocytic bulin immunoglobulin). It is used in rejection of the transplant, transplantation of organs, aplastic anaemia Аzathioprin Immunodepressant (synthetic cytostatic-antimetabolite). It is used for prevention the tissue incompatibility when transplanting organs, in autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.) Daclizumab Immunodepressant (monoclonal antibodies to interleukin-2 receptors). It suppresses interleukin-2-dependent proliferation of T- lymphocytes, inhibits the immune response to antigens. It is used to prevent rejection of a kidney while transplantation Cyclosporin Immunodepressant (antibiotic). Cyclic peptide that inhibits production of interleukin-2, and it leads to decrease of differentiation and proliferation of T-lymphocytes. It is used in transplantation of organs, the bone marrow transplantation, autoimmune diseases

Ethyl alcohol (Ethanol)

Pharmacodynamics (effects) → Indications Locally: Antibacterial, antiseptic Disinfection of the injection’s site, instruments and hands Irritating As a part of rubbing, compresses in inflammatory diseases of the locomotor organs Resorptively: Foam-extinguishing Pulmonary edema (as inhalation) Antishock Shock (seldom) Antidote in poisonings by methanol (inhibition Poisoning by methanol of highly toxic formaldehyde formation)

189 Ethyl alcohol is of the limited interest for medical practice. It is applied mainly as a preservative in the pharmaceutical industry and as an antiseptic. High concentrations of the alcohol locally cause protein denaturation of the skin and mucous membranes. Its negative resorptive action is connected with the influence on the central nervous system as it causes dose-dependent action: the CNS stimulation (euphoria) → the CNS inhibition (hypnotic effect, analgesia) → narcosis. The alcohol is not used as general anesthetic and analgesic because of the narrow interval of the therapeutic action. It causes addiction, mental and physical dependence, chronic poisoning (alcoholism). As the result of inhibition of antidiuretic hormone formation, diuresis increases. It influences on the thermoregulation (increase of heat emission, vasodilation, heat loss, feeling of heat), increases salivary and digestive glands secretion (reflex and direct action on glands), decreases the stomach motility

190 THE LIST OF ABBREVIATIONS

aer. Aerosol ACE Angiotensin-converting enzyme ACh Acetylcholine ACTH Adrenocorticotropic hormone ADH Antidiuretic hormone AIDS Acquired immune deficiency syndrome amp. Ampoules AR Adrenoreceptors ARVI Acute respiratory viral infections ASA Acetylsalicylic acid ATP Adenosine triphosphate BA Bronchial asthma BAS Biologically active substances BBB Blood-brain barrier CG Cardiac glycosides BHP Benign hyperplasia of prostate cAMP Cyclic adenosine monophosphate caps. Capsules ChR Cholinoreceptors CS Cholesterol CNS Central nervous system COG Cyclooxygenase COMT Catechol-O-methyltransferase BP Blood pressure CSF Colony-stimulating factor DNA Deoxyribonucleic acid dr. Drage EH Essential hypertension extr. Extract for inj. For injections FSH Follicle-stimulating hormone GABA Gamma-aminobutyric acid GC Glucocorticosteroids GIT Gastro-intestinal tract HC Hypertensive crisis h/chl. Hydrochloride HDLP High density lipoproteins HF Heart failure HIV Human immunedeficiency virus ICP Intracranial pressure IHD Ischemic heart disease INN International name i/m intramuscularly

191 IOP Intraocular pressure i/v Intravenously LDLP Low density lipoproteins LH LTH Lactotropic hormone lyoph. Lyophilised MAO Monoamine-oxidase MC Mineral corticosteroids MCSH Melanocyte-stimulating hormone MI Myocardial infarction NA Noradrenaline NNA Non-narcotic analgesics NSAIDs Non-steroidal anti-inflammatory drugs OA Opioid analgesics OR Opiate (opioid) receptors PABA Para-aminobenzoic acid PASA Para-aminosalicylic acid PG Prostaglandins pwd. Powder RNA Ribonucleic acid s/c subcutaneous sol. Solution STH Somatotropic hormone supp. Suppository susp. Suspension tabl. Tablets TG Triglyceride tinct. Tincture TPVR Total peripheral vascular resistance TTH Thyrotropic hormone VLDLP Very low density lipoproteins  Decrease  Increase

192